Cyanomethylpyrazole carboxamides as janus kinase inhibitors

ABSTRACT

The instant invention provides compounds of formula I which are JAK inhibitors, and as such are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application No. PCT/US2012/056478, filed Sep. 21, 2012, which claims priority under 35 U.S.C. §119(e) from U.S. Provisional Application Ser. No. 61/537,978, filed Sep. 21, 2011.

BACKGROUND OF THE INVENTION

Protein kinases are a group of enzymes that regulate the activity of their target proteins by the addition of phosphate groups to the protein substrate. Kinases play an essential role in many physiological processes including cell division, differentiation, cellular homeostasis and signal transduction. Kinases can be subdivided by their target into Serine/Threonine kinases and Tyrosine kinases. Tyrosine kinases are further subdivided into receptor tyrosine kinases and non-receptor tyrosine kinases. The mammalian Janus kinase (JAK) family members are non-receptor tyrosine kinases.

The JAK family has four members; JAK1, JAK2, JAK3 and TYK2. JAK1, JAK2 and TYK2 are universally expressed, whereas JAK3 expression is limited to hematopoetic cells. The JAK family is involved in intracellular signal transduction from >70 different cytokines. Cytokines bind to their cell surface receptors resulting in receptor dimerization and subsequent activation/phosphorylation of JAK tyrosine kinases. The JAKs are either constitutively associated with the receptor or are recruited upon cytokine binding. Specific tyrosine residues on the receptor are then phosphorylated by activated JAKs and serve as docking sites for STAT proteins. STATs are phosphorylated by JAKs, dimerize, then translocate to the nucleus where they bind specific DNA elements and activate gene transcription. JAK1 signals in conjunction with all JAK isoforms in a cytokine dependent manner.

JAKs are essential for multiple physiological functions. This has been demonstrated using genetically engineered mouse models that are deficient in specific JAKs. Jak1^(−/−) mice die perinatally, while Jak2^(−/−) mice have deficiencies in erythropoesis and die around day E12. Jak3^(−/−) mice are viable, but have a SCID phenotype with deficiencies in T cells, B cells and NK cells. TYK2^(−/−) mice exhibit features of hyper IgE syndrome. These phenotypes demonstrate the essential and non-redundant roles of JAK activity in vivo (K. Ghoreschi, A. Laurence, J. J. O'Shea, Immunol. Rev. 228, 273 (2009)).

Furthermore, mutations in the JAK enzymes have been associated with diseases in humans. Inactivating mutations in JAK3 (or the cognate common gamma chain cytokine receptor) cause a severe SCID phenotype (J. J. O'Shea, M. Pesu, D. C. Borie, P. S. Changelian, Nat. Rev. Drug Discov. 3, 555 (2004)). Deletions of TYK2 result in hyper IgG syndrome and increased infection risk (Y. Minegishi et al., Immunity. 25, 745 (2006)). No inactivating mutations have been reported for JAK1 or JAK2, consistent with the data from mice that demonstrates that JAK1 and JAK2 deficient mice are not viable. However, several mutations that result in constitutively active JAK2 have been identified, resulting in myeloproliferative diseases and confirming the central role of JAK2 in hematopoesis (O. bdel-Wahab, Curr. Opin. Hematol. 18, 117 (2011)). JAK2 is the sole JAK family member involved in signal transduction of the critical hematopoetic cytokines IL-3, GMCSF, EPO and TPO.

The wealth of mouse and human genetic data demonstrating a central role for JAK kinase activity in autoimmune disease, hematopoesis and oncology has been supported by the use of pan-JAK inhibitors in clinical trials for autoimmune diseases and neoplasms (See K. Ghoreschi, et al, Immunol. Rev. 228, 273 (2009), and A. Quintas-Cardama, H. Kantarjian, J. Cortes, S. Verstovsek, Nat. Rev. Drug Discov. 10, 127 (2011)). However, several adverse events have been reported that may be associated with inhibition of JAK2 signaling such as anemia, neutropenia and thrombocytopenia. Thus new or improved agents that selectively inhibit JAK1 activity but spare JAK2 activity are required for the treatment of several human diseases with an improved therapeutic index.

A considerable body of literature has accumulated that link the Jak/STAT pathway to various diseases and disorders including hyperproliferative disorders and cancer such as leukemia and lymphomas, immunological and inflammatory disorders such as transplant rejection, asthma, chronic obstructive pulmonary disease, allergies, rheumatoid arthritis, type I diabetes, amyotropic lateral sclerosis and multiple sclerosis.

SUMMARY OF THE INVENTION

The present invention provides novel compounds which are inhibitors of JAKs. The invention also provides a method for the treatment and prevention of JAK-mediated diseases and disorders using the novel compounds, as well as pharmaceutical compositions containing the compounds.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of formula I or pharmaceutically acceptable salts, or stereoisomers thereof:

R^(a) and R⁴ are each independently selected from hydrogen and C₁₋₄alkyl; A is selected from aryl, and heteroaryl; n is independently 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; X is independently selected from C, N, O and S; R³ and R⁷ are each independently selected from

hydrogen,

halogen,

C₁₋₁₀ alkyl,

C₂₋₁₀ alkenyl,

C₁₋₁₀ heteroalkyl,

aryl C₀₋₁₀ alkylC₀₋₁₀ alkyl,

C₃₋₈ cycloalkylC₀₋₁₀ alkyl,

heteroaryl C₀₋₁₀ alkyl,

(C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl,

and wherein each of R³ and R⁷ are independently substituted with 0, 1, 2, 3, or 4 R^(5a) substituents;

R^(5a) is selected from:

halogen,

C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

C₁₋₁₀ heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

aryl C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

aryl C₂₋₁₀ alkynyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

(C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

C₁₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,

C₁₋₁₀ heteroalkyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl,

C₂₋₁₀ alkenyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,

C₁₋₁₀ hetero alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,

aryl C₀₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,

(C₃₋₈)cycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,

heteroarylC₀₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,

(C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,

((C₀₋₁₀)alkyl)₁₋₂aminocarbonyloxy,

(C₀₋₁₀)heteroalkylaminocarbonyloxy,

aryl (C₀₋₁₀)alkylaminocarbonyloxy,

(C₃₋₈)cycloalkyl(C₀₋₁₀)alkylaminocarbonyloxy,

heteroaryl(C₀₋₁₀)alkylaminocarbonyloxy,

(C₃₋₈)heterocycloalkyl(C₀₋₁₀)alkylaminocarbonyloxy,

C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

(C₀₋₁₀)heteroalkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

C₃₋₈cycloalkyl C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

aryl C₀₋₁₀alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

heteroarylC₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

(C₃₋₈)heterocycloalkylC₀₋₁₀alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl,

C₁₋₁₀ heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl,

C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl,

aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl,

heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl))₀₋₁ aminoC₀₋₁₀ alkyl,

(C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl,

—CO₂(C₀₋₁₀ alkyl),

—(C₀₋₁₀ alkyl)CO₂H,

Oxo (═O);

C₁₋₁₀ alkylsulfonyl,

C₁₋₁₀ heteroalkylsulfonyl,

(C₃₋₈) cycloalkylsulfonyl,

(C₃₋₈) cycloheteroalkylsulfonyl,

heteroarylsulfonyl,

arylsulfonyl,

aminosulfonyl,

—SO₂N(C₁₋₆alkyl)₁₋₂,

—SO₂C₁₋₆alkyl,

—SO₂CF₃,

—SO₂CF₂H,

C₁₋₁₀ alkylsulfinyl,

—Si(CH₃)₃,

amino,

(C₀₋₁₀ alkyl)₁₋₂ amino,

C₁₋₄ acylamino C₀₋₁₀ alkyl,

hydroxy,

(C₁₋₁₀ alkyl)OH,

C₀₋₁₀ alkylalkoxy,

cyano,

(C₁₋₆alkyl)cyano, and

C₁₋₆ haloalkyl;

wherein two R^(5a) and the atom to which they are attached may optionally form a −4, −5, or −6 member saturated ring system;

wherein R^(5a) is each optionally substituted with 1, 2, 3, or 4 R⁶ substituents and R⁶ is independently selected from:

halogen,

C₁₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,

C₁₋₁₀ heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

aryl C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

aryl C₂₋₁₀ alkynyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

(C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,

C₁₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,

C₂₋₁₀ alkenyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,

C₁₋₁₀ heteroalkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,

aryl C₀₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,

(C₃₋₈)cycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,

heteroarylC₀₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,

(C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,

((C₀₋₁₀)alkyl)₁₋₂aminocarbonyloxy,

aryl (C₀₋₁₀)alkylaminocarbonyloxy,

(C₃₋₈)cycloalkyl(C₀₋₁₀)alkylaminocarbonyloxy,

heteroaryl(C₀₋₁₀)alkylaminocarbonyloxy,

(C₃₋₈)heterocycloalkyl(C₀₋₁₀)alkylaminocarbonyloxy,

C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

C₃₋₈ cycloalkyl C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

aryl C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

heteroaryl C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

(C₃₋₈)heterocycloalkyl C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

C₁₋₁₀ alkyl(oxy)₀₋₁carbonylaminoC₀₋₁₀ alkyl,

C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁carbonylaminoC₀₋₁₀ alkyl,

aryl C₀₋₁₀ alkyl(oxy)₀₋₁carbonylaminoC₀₋₁₀ alkyl,

heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁carbonylaminoC₀₋₁₀ alkyl,

(C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁carbonylaminoC₀₋₁₀ alkyl,

—CO₂(C₀₋₁₀ alkyl),

—(C₀₋₁₀ alkyl)CO₂H,

Oxo (═O),

C₁₋₁₀ alkylsulfonyl,

C₁₋₁₀ heteroalkylsulfonyl,

(C₃₋₈) cycloalkylsulfonyl,

(C₃₋₈) cycloheteroalkylsulfonyl,

heteroarylsulfonyl,

arylsulfonyl,

aminosulfonyl,

—SO₂N(C₁₋₆ alkyl)₁₋₂,

—SO₂C₁₋₆ alkyl,

—SO₂CF₃,

—SO₂CF₂H,

C₁₋₁₀ alkylsulfinyl,

—OSi(C₁₋₁₀alkyl)₃,

—Si(CH₃)₃,

amino,

(C₀₋₁₀ alkyl)₁₋₂ amino,

-(oxy)₀₋₁(carbonyl)₀₋₁N(C₀₋₁₀ alkyl)₁₋₂

C₁₋₄ acylamino C₀₋₁₀ alkyl,

hydroxy,

(C₁₋₁₀ alkyl)OH,

C₁₋₁₀ alkoxy,

(C₁₋₁₀ alkyl)cyano,

cyano, and

C₁₋₆haloalkyl; and

wherein two R⁶ and the atoms to which they are attached may optionally form a 3-, 4-, 5-, or 6-membered saturated ring system; and

R⁶ is optionally substituted with 1, 2, or 3 substituents selected from hydrogen, hydroxy, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₁₋₁₀ alkyl)OH, halogen, CO₂H, —(C₀₋₆)alkylCN, —O(C═O)C₁-C₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy, trifluoromethyl, trifluoroethyl, —N—C(O)O(C₀₋₆)alkyl, C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, oxo (O═), (C₃₋₈) cycloalkylsulfonyl, (C₃₋₈) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, —SO₂N(C₁₋₆alkyl)₁₋₂, —SO₂C₁₋₆alkyl, —SO₂CF₃, —Si(CH₃)₃, —SO₂CF₂H, —C₁₋₁₀ alkylsulfinyl, —OSi(C₁₋₁₀alkyl)₃, —O₍₀₋₁₎(C₁₋₁₀)haloalkyl, amino(C₁₋₆alkyl)₀₋₂ and NH₂; with the proviso that the compound of formula I other than:

-   1-[3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl]-3-({4-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenyl}amino)-1H-pyrazole-4-carboxamide;     and -   1-[3-(cyanomethyl)-1-(naphthalene-2-ylsulfonyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide.

Representative compounds of the instant invention include, but are not limited to the following compounds and their pharmaceutically acceptable salts and stereoisomers thereof:

-   tert-Butyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{3-[(4-bromophenyl)amino]-4-carbamoyl-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   tert-butyl     4-(3-{[3-(1H-benzotriazol-1-ylmethyl)phenyl]amino}-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     3-(4-carbamoyl-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate; -   tert-butyl     4-[4-carbamoyl-3-({4-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenyl}amino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-[4-carbamoyl-3-(pyridin-4-ylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     3-[4-carbamoyl-3-({4-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenyl}amino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   tert-Butyl-4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)-3-methylpiperidine-1-carboxylate; -   1-[3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl]-3-({4-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)cyclohexyl]-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)cyclohexyl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   tert-butyl     3-(4-carbamoyl-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazol-1-yl)-3-(cyanomethyl)pyrrolidine-1-carboxylate; -   tert-butyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)pyrrolidine-1-carboxylate; -   tert-butyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)cyclohexanecarboxylate; -   tert-butyl     {4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)cyclohexyl}carbamate; -   1-[3-(cyanomethyl)oxetan-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-(3-cyano-1-(cyanomethyl)cyclobutyl)-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-(3-cyano-1-(cyanomethyl)cyclobutyl)-3-((4-(methylsulfonyl)phenyl)amino)-1H-pyrazole-4-carboxamide; -   tert-butyl     6-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-6-(cyanomethyl)-2-azaspiro[3.3]heptane-2-carboxylate; -   1-[4-(Cyanomethyl)-1-(3,4-dimethoxyphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-isoquinolin-4-ylpiperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-quinolin-4-ylpiperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2-methylpyridin-4-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(5-fluoropyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2-methoxypyridin-4-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[5-(trifluoromethyl)pyridin-3-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[6-(2-hydroxyethoxy)pyridin-2-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4-fluoro-3-methoxyphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3-fluoro-5-methoxyphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[6-(difluoromethoxy)pyridin-3-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(5,6-dimethylpyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[6-(1-methylethoxy)pyridin-2-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(6-ethoxypyridin-2-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3-cyclopropylphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(6-cyanopyridin-2-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[5-(difluoromethoxy)pyridin-2-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(6-methylpyridin-2-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(5-cyanopyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(6-fluoropyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3-methoxypyridin-2-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1     [4-(cyanomethyl)-1-pyrimidin-5-ylpiperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2-methoxypyrimidin-5-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4-cyanophenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3-fluorophenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[6-(trifluoromethyl)pyridin-3-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2-methylpyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-pyridin-3-ylpiperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4-methylpyridin-2-yl)piperidin-4-yl]-3     [(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(5-fluoro-2-methylphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4-methylpyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3-fluoro-4-methylphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   methyl     6-[4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidin-1-yl]pyridine-2-carboxylate; -   1-[4-(cyanomethyl)-1-(6-ethoxypyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(5-methoxypyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4-fluorophenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4-methylphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3,5-difluorophenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2-methoxyphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4-fluoro-3-methylphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2-fluoro-3-methylphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4-fluoropyridin-2-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3,4-difluorophenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-pyridin-4-ylpiperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4-methylpyrimidin-5-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(5-methylpyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[6-(fluoromethyl)pyridin-2-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2-fluoropyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(6-methylpyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(6-methoxypyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(6-fluoropyridin-2-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[4-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(6-fluoro-5-methylpyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   tert-Butyl     4-(4-carbamoyl-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-[4-carbamoyl-3-({4-[(1-methylethoxy)carbonyl]phenyl}amino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-{[3-(1H-imidazol-1-ylmethyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2,2-trifluoroethyl     4-(3-{[3-(1H-benzotriazol-1-ylmethyl)phenyl]amino}-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   1-[4-(cyanomethyl)tetrahydro-2H-pyran-4-yl]-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carboxamide; -   tert-butyl     4-{4-carbamoyl-3-[(2-cyanopyrimidin-5-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-Butyl     4-(4-carbamoyl-3-((4-fluorophenyl)amino)-1H-pyrazol-1-yl)-4-(1-cyanoethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-[cyano(cyclopropyl)methyl]piperidine-1-carboxylate; -   tert-butyl-4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate; -   1-[4-(cyanomethyl)tetrahydro-2H-pyran-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[8-(cyanomethyl)-1,4-dioxaspiro[4.5]dec-8-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[8-(cyanomethyl)-1,4-dioxaspiro[4.5]dec-8-yl]-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carboxamide; -   1-(4-(Cyanomethyl)tetrahydro-2H-thiopyran-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide; -   1-(4-(Cyanomethyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide; -   tert-Butyl     4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-{[4-(methoxycarbonyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-Butyl 4-[4-(aminocarbonyl)-34     {4-[(methylamino)carbonyl]phenyl}amino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(4-cyanophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-(6-(2-hydroxypropan-2-yl)pyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-(6-(1-hydroxyethyl)pyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-(4-(2-hydroxypropan-2-yl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-(4-(1-hydroxyethyl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(3-(4-acetylphenylamino)-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-{[4-(trifluoroacetyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(6-cyanopyridin-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-{[4-(1-methyl-1H-pyrazol-3-yl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{3-[(2-aminopyridin-4-yl)amino]-4-carbamoyl-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-[4-carbamoyl-3-({4-[(trifluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-[4-carbamoyl-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(2-methylpyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-{[2-(hydroxymethyl)pyridin-4-yl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(2-methoxypyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(4-sulfamoylphenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-{[4-(dimethylsulfamoyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-{[4-(dimethylcarbamoyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-{[3-fluoro-4-(morpholin-4-ylcarbonyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-{[4-(morpholin-4-ylcarbonyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(4-cyano-3-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(2-carbamoylpyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(3,4-difluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(2-chloropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-{[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(2,6-dichloropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(2-cyanopyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-[4-carbamoyl-3-(pyridin-3-ylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(5-fluoropyridin-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(5-chloropyridin-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2-difluoroethyl     4-(4-carbamoyl-3-{[6-(cyclobutyloxy)pyridin-3-yl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2-difluoroethyl     4-{4-carbamoyl-3-[(6-cyclobutylpyridin-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2-difluoroethyl     4-{4-carbamoyl-3-[(2-methoxypyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2-difluoroethyl     4-{4-carbamoyl-3-[(6-cyclopropylpyridin-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2-difluoroethyl     4-{4-carbamoyl-3-[(2-cyclopropylpyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2,2-Trifluoroethyl     4-(4-carbamoyl-3-(6-(2-hydroxypropan-2-yl)pyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2,2-trifluoroethyl     4-(4-carbamoyl-3-(4-(trifluoromethylsulfonyl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2,2-trifluoroethyl     4-(4-carbamoyl-3-(6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2,2-trifluoroethyl     4-(3-(3-(1H-pyrazol-3-yl)phenylamino)-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2,2-trifluoroethyl     4-(4-carbamoyl-3-(3-(1-methyl-1H-pyrazol-4-yl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2,2-trifluoroethyl     4-(4-carbamoyl-3-(5-(1-methyl-1H-pyrazol-4-yl)pyridinl-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2,2-trifluoroethyl     4-(4-carbamoyl-3-(pyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2,2-trifluoroethyl     4-(4-carbamoyl-3-(5-fluoropyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2,2-trifluoroethyl     4-{4-carbamoyl-3-[(5-chloropyridin-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2,2-Trifluoroethyl     4-(4-carbamoyl-3-{[6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2,2-trifluoroethyl     4-(4-carbamoyl-3-{[6-(1H-pyrazol-4-yl)pyridin-3-yl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-Butyl     4-{3-[(3-bromophenyl)amino]-4-carbamoyl-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-{[4-(2-methoxy-2-oxoethyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(3,5-difluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-{[6-(morpholin-4-yl)aphthal-3-yl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(6-fluoropyridin-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-[4-carbamoyl-3-(pyridazin-4-ylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-Butyl     4-(4-carbamoyl-3-(pyrimidin-4-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-(6-methylpyridin-2-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-(pyridin-2-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-(5-fluoropyridin-2-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-(4-fluoropyridin-2-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-(pyridazin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-(pyrazine-2-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-(6-methylpyrazine-2-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-(6-methoxypyridin-2-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-(2,6-dimethylpyrimidin-4-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-(6-methylpyrimidin-4-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(4-carbamoyl-3-((5-fluoropyridin-3-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-Butyl     4-(4-carbamoyl-3-{[4-(3,5-dimethylisoxazol-4-yl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-Butyl     4-{4-carbamoyl-3-[(4′-chlorobiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(4′-fluorobiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-[3-(biphenyl-3-ylamino)-4-carbamoyl-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(4′-methoxybiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(4′-hydroxybiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(4′-methylbiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(2′-methylbiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(3′-chlorobiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(3-naphthalen-2-ylphenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(2′-fluorobiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(2′-hydroxybiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   [4-({1-[1-(tert-Butoxycarbonyl)-4-(cyanomethyl)piperidin-4-yl]-4-carbamoyl-1H-pyrazol-3-yl}amino)phenyl]acetic     acid; -   1-[3-(Cyanomethyl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[3-(Cyanomethyl)-1-methylazetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[1-(Biphenyl-4-ylmethyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(pyridin-3-ylmethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[1-(3-cyanobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[1-(4-cyanobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3-cyanopropyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[1-(2-chlorobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4-methylbenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(naphthalene-1-ylmethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(cyclohexylmethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[1-(1,3-benzodioxol-5-ylmethyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3-hydroxybenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{1-[4-(acetylamino)benzyl]-4-(cyanomethyl)piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(6-methoxynaphthalen-2-yl)methyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2,6-dichlorobenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[3-(methylsulfanyl)propyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2-ethoxybenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(2E)-3-phenylprop-2-en-1-yl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3-fluorobenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[4-(trifluoromethyl)benzyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[1-(1-benzofuran-2-ylmethyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[1-(4-chloro-2-fluorobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4-propylbenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2,6-difluorobenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[4-(1-methylethyl)benzyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3-phenylprop-2-yn-1-yl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2,3,6-trifluorobenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[4-(1-methylethoxy)benzyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3,4-dimethylbenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   methyl     2-({4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidin-1-yl}methyl)benzoate; -   1-(4-(Cyanomethyl)-1-((1-ethyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(pyridin-3-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(cyclohexylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(4-methyl-1H-imidazol-2-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1H-pyrazol-4-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(cyclohexylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-benzyl-4-(cyanomethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-benzyl-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2-fluorobenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3-fluorobenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4-fluorobenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1H-pyrazol-5-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(pyrazin-2-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(2-methyl-1,3-thiazol-5-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(pyrazolo[1,5-a]pyridin-3-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(furan-2-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1H-indol-5-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1H-indol-7-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(2-fluoro-5-methylpyridin-3-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(2-fluoropyridin-3-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-{[3-(1-hydroxy-1-methylethyl)cyclobutyl]methyl}piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1,3-oxazol-4-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(5-methylisoxazol-3-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1,3-oxazol-2-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(1-methyl-1H-pyrazol-5-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(1-methyl-1H-pyrazol-3-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(isoxazol-3-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(6-fluoropyridin-2-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(pyrazolo     pyridin-7-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(pyrazolo[1,5-a]pyridin-2-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(pyridazin-3-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(5-fluoropyridin-2-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(3-methoxycyclobutyl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(5-fluoropyridin-3-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1H-indol-2-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(1H-benzimidazol-2-ylmethyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1H-indol-2-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(2-fluoro-5-methylpyridin-3-yl)methyl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(isoxazol-3-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(6-fluoropyridin-2-yl)methyl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(pyridazin-3-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(5-fluoropyridin-2-yl)methyl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(5-fluoropyridin-3-yl)methyl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(4-fluoropyridin-2-yl)methyl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(pyridin-3-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(pyrazin-2-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(furan-2-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1H-indol-5-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1H-indol-6-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1H-indol-4-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1H-indol-7-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(2-chlorobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4-hydroxybenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(3-chlorobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(3-cyanobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3-methoxybenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2-phenylethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4-methoxybenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2-methoxybenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(6-oxo-1,6-dihydropyridin-2-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(6-hydroxypyridin-3-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(4-cyanobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3-hydroxybenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(4-chlorobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(2-cyanobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-(4-(Cyanomethyl)-1-(1-phenylethyl)piperidin-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide; -   1-(4-(Cyanomethyl)-1-(2-fluoroethyl)piperidin-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(cyclopropylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-(4-(Cyanomethyl)-1-(pyridin-2-yl)piperidin-4-yl)-3-(4-fluorophenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(Cyanomethyl)-1-pyrimidin-4-ylpiperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   Methyl     4-(4-carbamoyl-3-(4-(trifluoromethylsulfonyl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2-methoxyethyl     4-(4-carbamoyl-3-(4-(trifluoromethylsulfonyl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   methyl     4-(4-carbamoyl-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   benzyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   methyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   2-Methoxy-1,1-dimethylethyl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   1-Hydroxy-2-methylpropan-2-yl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2,2-Trifluoroethyl     4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2,2-trifluoroethyl     4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   1,1,1-trifluoropropan-2-yl     4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   cyclobutyl     4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   cyclobutylmethyl     4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   (2,2-difluorocyclopropyl)methyl     4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2-difluoroethyl     4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   (1-methylcyclopropyl)methyl     4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   1,3-difluoropropan-2-yl     4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   (trimethylsilyl)methyl     4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2-difluoro-3-hydroxypropyl     4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   1-cyclopropylethyl     4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   (1-hydroxycyclopropyl)methyl     4-(4-carbamoyl-3-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   1,1,1-trifluoropropan-2-yl     4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2-difluoroethyl     4-(4-carbamoyl-3-fluoropyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tetrahydrofuran-3-yl     4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tetrahydro-2H-pyran-4-yl     4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   oxetan-3-yl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   cyclopropylmethyl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   (3-methyloxetan-3-yl)methyl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tetrahydro-2H-pyran-4-ylmethyl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tetrahydrofuran-3-ylmethyl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   1-methoxypropan-2-yl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   2-methoxypropyl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tetrahydro-2H-pyran-3-yl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   oxetan-3-yl     4-(4-carbamoyl-3-(4-(trifluoromethylsulfonyl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2-difluoroethyl     4-(4-carbamoyl-3-(2-fluoropyridin-4-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2-methylpropyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2-dimethylpropyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   cyclopentyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   cyclohexyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   3-fluorobenzyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   2-fluorobenzyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   2,3-dihydro-1H-inden-2-yl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   2-methoxyethyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   4-carbamoyl-1-[4-(cyanomethyl)-1-{[tetrahydrofuran-3-yloxy]carbonyl}piperidin-4-yl]-3-(phenylamino)-1H-pyrazol-2-ium; -   tetrahydro-2H-pyran-4-yl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   pyridin-3-ylmethyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   pyridin-3-ylmethyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   pyridin-4-ylmethyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   2-morpholin-4-ylethyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   1-methylpiperidin-4-yl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   2-(4-methylpiperazin-1-yl)ethyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   (1-methylpiperidin-4-yl)methyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   3,3,3-Trifluoropropyl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tetrahydrofuran-3-yl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tetrahydro-2H-pyran-4-yl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   2-methoxyethyl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   Cyclopropylmethyl     4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   2-fluoroethyl 3-[4-carbamoyl-3-(phenylamino)-1H     pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   2-methylpropyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   cyclopentyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   benzyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   2-naphthalen-1-ylethyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   2-morpholin-4-ylethyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   2,2-dimethylpropyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   cyclohexyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   2-phenylethyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   2-methoxyethyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   2-ethoxy-2-oxoethyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   3-methoxypropyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   tetrahydrofuran-3-yl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   tetrahydro-2H-pyran-4-yl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   2-(2-oxopyrrolidin-1-yl)ethyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   pyridin-3-ylmethyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   pyridin-4-ylmethyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   2-pyridin-2-ylethyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   3-pyridin-3-ylpropyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   2-methoxybenzyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   3-methoxybenzyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   3-(dimethylamino)propyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   2-(4-methylpiperazin-1-yl)ethyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   (1-methylpiperidin-4-yl)methyl     3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; -   cyclopentyl     3-(4-carbamoyl-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate; -   tetrahydrofuran-3-yl     3-(4-carbamoyl-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate; -   tetrahydro-2H-pyran-4-yl     3-(4-carbamoyl-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate; -   1-cyclopropylethyl     4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   2-Hydroxy-1-methylethyl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   1-[1-Acetyl-3-(cyanomethyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(Cyanomethyl)-1-propanoylpiperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{1-[(2E)-but-2-enoyl]-4-(cyanomethyl)piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(Cyanomethyl)-1-(cyclopropylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(methoxyacetyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-pentanoylpiperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(N,N-dimethylglycyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(phenylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(pyridin-3-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(pyridin-2-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(pyridin-4-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(pyrazin-2-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(cyclohexylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(thiophen-2-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(2-oxopyrrolidin-1-yl)acetyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(thiophen-3-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(2E)-3-pyridin-3-ylprop-2-enoyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(4-methoxyphenyl)carbonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{1-[(4-chlorophenyl)carbonyl]-4-(cyanomethyl)piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{1-[(2-chlorophenyl)carbonyl]-4-(cyanomethyl)piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{1-[(3-chlorophenyl)carbonyl]-4-(cyanomethyl)piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(1H-indol-2-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-[4-(dimethylamino)phenyl]carbonyl     piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(4-methoxyphenyl)acetyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(naphthalene-1-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(1-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(3,4-dimethoxyphenyl)carbonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(3-morpholin-4-ylphenyl)carbonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[1-(biphenyl-2-ylcarbonyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-{[4-(trifluoromethyl)phenyl]acetyl}piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(4-morpholin-4-ylphenyl)carbonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(quinolin-2-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(diphenylacetyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-{[4-(4-methylpiperazin-1-yl)phenyl]carbonyl}piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(hydroxyacetyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[3-(cyanomethyl)-1-propanoylazetidin-3-yl]-3-(phenylamino)-1H     pyrazole-4-carboxamide; -   1-[3-(cyanomethyl)-1-(2,2-dimethylpropanoyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[3-(cyanomethyl)-1-(pyridin-2-ylcarbonyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(tetrahydrofuran-2-ylacetyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2,2-difluoropropanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[3-fluoro-2-(fluoromethyl)-2-methylpropanoyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(methoxyacetyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(cyclopropylacetyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(2R)-2-hydroxy-3-methylbutanoyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(2S)-2-hydroxy-3-methylbutanoyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3,3,3-trifluoro-2-methylpropanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanoacetyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3-hydroxy-3-methylbutanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-{[1-(trifluoromethyl)cyclobutyl]carbonyl}piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyano     methyl)-1-(1H-imidazol-1-ylacetyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(3,3-difluorocyclobutyl)carbonyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyano     methyl)-1-(3,3-dimethylbutanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(3,3,3-trifluoro-2,2-dimethylpropanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-{[1-(trifluoromethyl)cyclopropyl]carbonyl}piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(methylsulfonyl)acetyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2,2-difluorobutanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(1-methylcyclobutyl)carbonyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyano     methyl)-1-(3,3-difluoro-2-hydroxy-2-methylpropanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(3R)-3-hydroxybutanoyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-(4-(Cyanomethyl)-1-(3,3,3-trifluoropropanoyl)piperidin-4-yl)-3-(4-fluorophenylamino)-1H-pyrazole-4-carboxamide; -   1-(4-(cyanomethyl)-1-(3,3,3-trifluoropropanoyl)piperidin-4-yl)-3-(2-fluoropyridin-4-ylamino)-1H-pyrazole-4-carboxamide; -   1-(4-(cyanomethyl)-1-(3,3,3-trifluoropropanoyl)piperidin-4-yl)-3-(5-fluoropyridin-3-ylamino)-1H-pyrazole-4-carboxamide; -   1-[1-(Cyanoacetyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[1-(cyanoacetyl)-4-(cyanomethyl)piperidin-4-yl]-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carboxamide; -   1-[4-(Cyanomethyl)-1-(isopropylsulfonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(methylsulfonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(ethylsulfonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(furan-2-ylsulfonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(trifluoromethyl)sulfonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(phenylsulfonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[1-(benzylsulfonyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(4-methoxyphenyl)sulfonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(3-methoxyphenyl)sulfonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{1-[(3-chlorophenyl)sulfonyl]-4-(cyanomethyl)piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{1-[(2-chlorophenyl)sulfonyl]-4-(cyanomethyl)piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide -   1-[4-(cyanomethyl)-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[1-(biphenyl-4-ylsulfonyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(cyclopropylsulfonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[3-(cyanomethyl)-1-(methylsulfonyl)azetidin-3-yl]-3-(phenylamino)-1H     pyrazole-4-carboxamide; -   1-[3-(cyanomethyl)-1-(furan-2-ylsulfonyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(trifluoromethyl)sulfonyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[3-(cyanomethyl)-1-(phenylsulfonyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[1-(benzylsulfonyl)-3-(cyanomethyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(Cyanomethyl)-1-[(3-fluorophenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H     pyrazole-4-carboxamide; -   1-[3-(cyanomethyl)-1-(cyclohexylcarbamoyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(1-methylethyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(3,4-dimethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[1-(butylcarbamoyl)-3-(cyanomethyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(4-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[3-(cyanomethyl)-1-{[4-(1-methylethyl)phenyl]carbamoyl}azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[3-(cyanomethyl)-1-{[2-(1-methylethyl)phenyl]carbamoyl}azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   ethyl     N-({3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidin-1-yl}carbonyl)alaninate; -   1-{3-(cyanomethyl)-1-[(2,5-difluorophenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(3-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(2,4,6-trimethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{1-[(3-chloro-4-methylphenyl)carbamoyl]-3-(cyanomethyl)azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{1-[(4-chloro-2-methylphenyl)carbamoyl]-3-(cyanomethyl)azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(4-cyanophenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(2,5-dimethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{1-[(5-chloro-2-methylphenyl)carbamoyl]-3-(cyanomethyl)azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[3-(cyanomethyl)-1-(propylcarbamoyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(2,4-dimethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(3,5-dimethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(3,4-difluorophenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{1-[(3-chloro-2-methylphenyl)carbamoyl]-3-(cyanomethyl)azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(2-ethyl-6-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{1-[(2-chloro-6-methylphenyl)carbamoyl]-3-(cyanomethyl)azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(2-methoxy-5-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(4-ethoxyphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(2-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(2,4-difluorophenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(1,1,3,3-tetramethylbutyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(2-ethoxyphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(2,6-dimethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{1-[(3-acetylphenyl)carbamoyl]-3-(cyanomethyl)azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[3-(cyanomethyl)-1-{[(1R)-1-phenylethyl]carbamoyl}azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(4-ethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(3-ethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(4-methoxy-2-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(3-fluoro-4-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(5-fluoro-2-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(2-ethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{1-[(3-chloro-4-fluorophenyl)carbamoyl]-3-(cyanomethyl)azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(4-methylphenyl)carbamoyl]azetidin-3-yl}-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carboxamide; -   1-{3-(cyanomethyl)-1-[(2,5-difluorophenyl)carbamoyl]azetidin-3-yl}-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carboxamide; -   1-[1-(butylcarbamoyl)-3-(cyanomethyl)azetidin-3-yl]-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carboxamide; -   4-(4-carbamoyl-3-(4-(trifluoromethylsulfonyl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-N-isopropylpiperidine-1-carboxamide; -   4-(4-carbamoyl-3-(4-(trifluoromethylsulfonyl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-N-(4-cyanophenyl)piperidine-1-carboxamide; -   4-[4-Carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)-N-(1-methylethyl)piperidine-1-carboxamide; -   4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)-N-(4-cyanophenyl)piperidine-1-carboxamide; -   3-((4-chlorophenyl)amino)-1-(1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(3-fluoro     azetidin-1-yl)cyclohexyl]-3-{[4-(trifluoromethyl)phenyl]amino}-1H-pyrazole-4-carboxamide; -   1-(1-(cyanomethyl)-4-(cyclohexylamino)cyclohexyl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(3-fluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(pyridin-2-ylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(pyridin-3-ylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(4-hydroxyphenyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(pyridin-3-ylamino)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(pyridin-3-ylamino)cyclohexyl]-34     {4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,5-difluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(2-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(pyridin-2-ylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(4-hydroxypiperidin-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(3-hydroxyphenyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[methyl(phenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(3-fluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2-fluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(4-fluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(4-fluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(3,4-difluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(2,3-dihydro-1H-indol-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(pyridin-2-ylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(cyclohexylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2-fluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(2-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(4-hydroxypiperidin-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(cyclohexylamino)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-{4-[(3-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(2,3-dihydro-1H-indol-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(4,4-difluoropiperidin-1-yl)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2-hydroxyphenyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,4-difluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[methyl(phenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(3,4-difluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(3,4-difluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,4-difluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(pyridin-3-ylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(4-fluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(4-hydroxypiperidin-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(4,4-difluoropiperidin-1-yl)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(4-hydroxypiperidin-1-yl)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(3-hydroxyphenyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-{4-[(4-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(3-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(4-fluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2-hydroxyphenyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(2,3-dihydro-1H-indol-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,5-difluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(cyclohexylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(4-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(4-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(2,3-dihydro-1H-indol-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(3-fluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(4-hydroxypiperidin-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(cyclohexylamino)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2-fluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(4-hydroxyphenyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2-fluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(4-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(3-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,5-difluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(3-fluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(4-hydroxypiperidin-1-yl)cyclohexyl]-34     {4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2-hydroxyethyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(cyclopropylmethyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(4,4-difluoropiperidin-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2-methoxyethyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-{methyl[2-(methylsulfonyl)ethyl]amino}cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-{[4-(trifluoromethyl)phenyl]amino}cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(3-methoxyazetidin-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(pyridin-3-ylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(4-acetylpiperazin-1-yl)-1-(cyanomethyl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,2-difluoroethyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(methylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2-fluoroethyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-azetidin-1-yl-1-(cyanomethyl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(3-methoxyazetidin-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(phenylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,2-difluoroethyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(phenylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,2-difluoroethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(phenylamino)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(1,3-dihydro-2H-isoindol-2-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-[4-(benzylamino)-1-(cyanomethyl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(3-methoxyazetidin-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(phenylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(4-cyanobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,2-difluoroethyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(phenylamino)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(phenylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,2-difluoroethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[cis-4-(benzylamino)-1-(cyanomethyl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-(1-(cyanomethyl)-4-((2,4-difluorobenzyl)amino)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide; -   1-[4-amino-1-(cyanomethyl)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,4-difluorobenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(3-hydroxybenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(4-cyanobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2-hydroxybenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1     H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(cyclohexylmethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(4-chlorobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(2-chlorobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2-fluorobenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(4-fluorobenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(pyridin-4-ylmethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(3-cyanobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(4-chlorobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(2-chlorobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(pyridin-2-ylmethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(benzylamino)-1-(cyanomethyl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(3-fluorobenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(3-chlorobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2-fluorobenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(pyridin-3-ylmethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(3-chlorobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(3-fluorobenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(4-fluorobenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(4-hydroxybenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(2-cyanobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(benzylamino)-1-(cyanomethyl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-(1-(Cyanomethyl)-4-(3-fluorophenylsulfonamido)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide; -   1-(4-(Cyanomethyl)-1-(2,2-difluoropropanoyl)-3-fluoropiperidin-4-yl)-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazole-4-carboxamide; -   1-(4-(cyanomethyl)-1-(2,2-difluoropropanoyl)-3-fluoropiperidin-4-yl)-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazole-4-carboxamide; -   1-(4-(cyanomethyl)-1-(2,2-difluoropropanoyl)-3-fluoropiperidin-4-yl)-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)carbamoyl]cyclohexyl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   2,2-Difluoroethyl 4-(4-carbamoyl-3     ((2-fluoropyridin-4-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate; -   1-(4-amino-1-(cyanomethyl)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide; -   4-amino-1-(cyanomethyl)cyclohexyl)-3-((4-((difluoromethyl)sulfonyl)phenyl)amino)-1H-pyrazole-4-carboxamide; -   tert-butyl-4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate; -   tert-butyl-4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)-3-methylpiperidine-1-carboxylate; -   tetrahydrofuran-3-yl     4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate;     and -   tetrahydrofuran-3-yl     4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate.

In one embodiment of the invention, representative compounds include, but are not limited to the following compounds and their pharmaceutically acceptable salts and stereoisomers thereof:

-   tert-Butyl     4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-Butyl-4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)-3-methylpiperidine-1-carboxylate, -   1-{4-(cyanomethyl)-1-[5-(trifluoromethyl)pyridin-3-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(4-methylphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   tert-butyl-4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate; -   tert-butyl-4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate; -   tert-Butyl     4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-{4-carbamoyl-3-[(2,6-dichloropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-Butyl     4-(4-carbamoyl-3-(pyrimidin-4-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   [4-({1-[1-(tert-Butoxycarbonyl)-4-(cyanomethyl)piperidin-4-yl]-4-carbamoyl-1H-pyrazol-3-yl}amino)phenyl]acetic     acid; -   1-{1-[4-(acetylamino)benzyl]-4-(cyanomethyl)piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(cyclohexylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(cyanomethyl)-1-(2-fluorobenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-(cyanomethyl)-1-[(5-fluoropyridin-3-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-[4-(Cyanomethyl)-1-pyrimidin-4-ylpiperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   2,2,2-Trifluoroethyl     4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2-difluoroethyl     4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2,2-difluoroethyl     4-(4-carbamoyl-3-(2-fluoropyridin-4-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   cyclopropylmethyl     4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   1-cyclopropylethyl     4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   1-[4-(cyanomethyl)-1-[4-(trifluoromethyl)phenyl]acetyl     piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; -   1-(4-(cyanomethyl)-1-(3,3,3-trifluoropropanoyl)piperidin-4-yl)-3-(4-fluorophenylamino)-1H-pyrazole-4-carboxamide; -   1-(4-(cyanomethyl)-1-(3,3,3-trifluoropropanoyl)piperidin-4-yl)-3-(2-fluoropyridin-4-ylamino)-1H-pyrazole-4-carboxamide; -   3-((4-chlorophenyl)amino)-1-(1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl]-3-{[4-(trifluoromethyl)phenyl]amino}-1H-pyrazole-4-carboxamide; -   1-[1-(cyanomethyl)-4-(cyclohexylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; -   1-{4-[(3-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; -   1-{1-(cyanomethyl)-4-[(cyclohexylmethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide;     and -   2,2-Difluoroethyl     4-(4-carbamoyl-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate.

The invention also encompasses pharmaceutical compositions containing a compound of formula I, and methods for treatment or prevention of JAK mediated diseases using compounds of formula I.

The invention is described using the following definitions unless otherwise indicated.

As used herein except where noted, “alkyl” is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbon atoms. Commonly used abbreviations for alkyl groups are used throughout the specification, e.g. methyl may be represented by “Me” or CH₃, ethyl may be represented by “Et” or CH₂CH₃, propyl may be represented by “Pr” or CH₂CH₂CH₃, butyl may be represented by “Bu” or CH₂CH₂CH₂CH₃, etc. “C₁₋₆ alkyl” (or “C₁-C₆ alkyl”) for example, means linear or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms. C₁₋₆ alkyl includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. “C₁₋₄ alkyl” means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. The term “alkylene” refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbons, and having two terminal end chain attachments. For illustration, the term “unsubstituted A-C₄alkylene-B” represents A-CH₂—CH₂—CH₂—CH₂—B. The term “alkoxy” represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge.

“Acyl” means a C(O)R radical Where R is optionally substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl heteroaryl, etc.

“Acylamino” means a NRR′ radical where R is H, OH, or alkoxy and R′ is acyl, as defined herein.

The term “alkyl” refers to an aliphatic hydrocarbon group which may be straight or branched and having the indicated number of carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, and the like.

The term “heteroalkyl” refers to an alkyl group where 1, 2, or 3 of the carbon atoms is substituted by a heteroatom independently selected from N, O, or S.

“Alkenyl” refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and having the indicated number of carbon atoms. Preferably alkenyl contains one carbon to carbon double bond, and up to four nonaromatic carbon-carbon double bonds may be present. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 2-methyl-1-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkynyl” refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and having the indicated number of carbon atoms. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.

“Alkoxy” refers to an alkyl-O— group in which the alkyl group is as described above. C₁₋₆ alkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.

“Alkoxyalkyl” refers to an alkyl group as described above in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by alkoxy groups. Examples include CH₂OCH₃, CH₂CH₂OCH₃ and CH(OCH₃)CH₃.

“Aminoalkyl” refers to an alkyl group as described above in which one hydrogen atom has been replaced by an amino, monoalkylamino or dialkylamino group. Examples include CH₂NH₂, CH₂CH₂NHCH₃ and CH(N(CH₃)₂)CH₃.

The term “C₀” as employed in expressions such as “C₀₋₆ alkyl” means a direct covalent bond; or when the term appears at the terminus of a substituent, C₀₋₆ alkyl means hydrogen or C₁₋₆alkyl. Similarly, when an integer defining the presence of a certain number of atoms in a group is equal to zero, it means that the atoms adjacent thereto are connected directly by a bond. For example, in the structure

wherein s is an integer equal to zero, 1 or 2, the structure is

when s is zero.

The term “C₃₋₈cycloalkyl” (or “C₃-C₈ cycloalkyl”) means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). The terms “C₃₋₇ cycloalkyl”, “C₃₋₆ cycloalkyl”, “C₅₋₇ cycloalkyl” and the like have analogous meanings.

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro (F), chloro (Cl), bromo (Br), and iodo (I)).

The term “aryl” refers to aromatic mono- and poly-carbocyclic ring systems, wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond. Suitable aryl groups include phenyl, naphthyl, 2,3-dihydro-1H-indenyl, and biphenyl.

The term “carbocycle” (and variations thereof such as “carbocyclic” or “carbocyclyl”) as used herein, unless otherwise indicated, refers to (i) a C₃ to C₈ monocyclic, saturated or unsaturated ring or (ii) a C₇ to C₁₂ bicyclic saturated or unsaturated ring system. Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated. The carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound. The fused bicyclic carbocycles are a subset of the carbocycles; i.e., the term “fused bicyclic carbocycle” generally refers to a C₇ to C₁₀ bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms are shared by each of the rings in the ring system. A fused bicyclic carbocycle in which one ring is saturated and the other is saturated is a saturated bicyclic ring system. A fused bicyclic carbocycle in which one ring is benzene and the other is saturated is an unsaturated bicyclic ring system. A fused bicyclic carbocycle in which one ring is benzene and the other is unsaturated is an unsaturated ring system. Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc. Unless otherwise noted, carbocycle is unsubstituted or substituted with C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, aryl, halogen, NH₂ or OH. A subset of the fused bicyclic unsaturated carbocycles are those bicyclic carbocycles in which one ring is a benzene ring and the other ring is saturated or unsaturated, with attachment via any carbon atom that results in a stable compound. Representative examples of this subset include the following:

“Cyanoalkyl” refers to an alkyl group as described above in which one hydrogen atom has been replaced by a cyano group. Examples include CH₂CN, CH₂CH₂CN and CH(CN)CH₃.

“Cycloalkyl” means a carbocyclic ring system having 3 to 12 ring carbon atoms; said ring system may be (a) a monocyclic saturated carbocycle optionally fused to a benzene or a partially unsaturated carbocycle, or (b) a bicyclic saturated carbocycle. For a bicyclic system, within either (a) or (b), the rings are fused across two adjacent ring carbon atoms (e.g., decalin), at one ring carbon atom (e.g., spiro[2.2]pentane), or are bridged groups (e.g., norbornane). Additional examples within the above meaning include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, perhydroindan, decalin, spiro[4.5]decane, bicyclo[2.2.2]octane, and the like.

“Haloalkyl” refers to an alkyl group as described above wherein one or more (in particular 1 to 5) hydrogen atoms have been replaced by halogen atoms, with up to complete substitution of all hydrogen atoms with halo groups. C₁₋₆haloalkyl, for example, includes —CF₃, —CF₂CF₃, CHFCH₃, and the like.

“Heterocycle”, “heterocyclic” or “heterocyclyl” represents a monocyclic or bicyclic 3-12 membered ring system in which at least one ring is non-aromatic (saturated or partially unsaturated) and containing at least one heteroatom selected from O, S and N. In a bicyclic ring system, the second ring may be a heteroaryl, heterocycle or a saturated, partially unsaturated or aromatic carbocycle, and the point(s) of attachment to the rest of the molecule may be on either ring. “Heterocyclyl” therefore includes heteroaryls, as well as dihydro and tetrathydro analogs thereof. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.

Examples of heterocycles (heterocyclyl) include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, dihydroimidazolyl, dihydroindolyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 2,3-dihydrobenzofuranyl, benzo-1,4-dioxanyl, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof.

Saturated heterocyclics form a subset of the heterocycles; i.e., the terms “saturated heterocyclic and (C₃₋₁₂)heterocycloalkyl” generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is saturated. The term “saturated heterocyclic ring” refers to a 4- to 8-membered saturated monocyclic ring or a stable 7- to 12-membered bicyclic ring system which consists of carbon atoms and one or more heteroatoms selected from N, O and S. Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl)

Heteroaromatics form another subset of the heterocycles; i.e., the term “heteroaromatic” (alternatively “heteroaryl”) generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is an aromatic ring system. The term “heteroaromatic ring” refers a 5- or 6-membered monocyclic aromatic ring or a 7- to 12-membered bicyclic which consists of carbon atoms and one or more heteroatoms selected from N, O and S. For a bicyclic heteroaryl only one of the rings need to be heteroaromatic, the second ring may be a heteroaromatic or an aromatic, saturated, or partially unsaturated carbocycle, and the point(s) of attachment to the rest of the molecule may be on either ring. In the case of substituted heteroaryl rings containing at least one nitrogen atom (e.g., pyridine), such substitutions can be those resulting in N-oxide formation. Examples of heteroaryl include, but are not limited to, furanyl, thienyl (or thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, naphthyridinyl, benzothienyl, benzofuranyl, benzimidazole, benzpyrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, benzisoxazolyl, 5,6,7,8-tetrahydroquinolinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-c]-pyrimidinyl, 5,6-dihydropyrrolo[1,2-b]pyrazolyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, thieno[2,3-b]pyrrolyl, furopyridine and thienopyridine.

Representative examples of bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dioxinyl (i.e.,

imidazo(2,1-b)(1,3)thiazole. (i.e.,

and benzo-1,3-dioxolyl (i.e.,

In certain contexts herein,

is alternatively referred to as phenyl having as a substituent methylenedioxy attached to two adjacent carbon atoms.

“Hydroxyalkyl” refers to an alkyl group as described above in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by hydroxy groups. Examples include CH₂OH, CH₂CHOH and CHOHCH₃.

“Alkylene,” “alkenylene,” “alkynylene,” “cycloalkylene,” “arylene,” “heteroarylene,” and “heterocyclylene” refer to a divalent radical obtained by the removal of one hydrogen atom from an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl group, respectively, each of which is as defined above.

Unless expressly stated to the contrary, an “unsaturated” ring is a partially or fully unsaturated ring. For example, an “unsaturated monocyclic C₆ carbocycle” refers to cyclohexene, cyclohexadiene, and benzene.

Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heterocycle described as containing from “1 to 4 heteroatoms” means the heterocycle can contain 1, 2, 3 or 4 heteroatoms.

When any variable occurs more than one time in any constituent or in any formula depicting and describing compounds of the invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term “substituted” (e.g., as in “aryl which is optionally substituted with one or more substituents . . . ”) includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed.

The term “oxy” means an oxygen (O) atom. The term “thio” means a sulfur (S) atom. The term “oxo” means “═O”. The term “carbonyl” means “C═O.”

Structural representations of compounds having substituents terminating with a methyl group may display the terminal methyl group either using the characters “CH₃”, e.g. “—CH₃” or using a straight line representing the presence of the methyl group, e.g. “

”, i.e.,

have equivalent meanings.

For variable definitions containing terms having repeated terms, e.g., (CR^(i)R^(j))_(r), where r is the integer 2, R^(i) is a defined variable, and R^(j) is a defined variable, the value of R^(i) may differ in each instance in which it occurs, and the value of R^(j) may differ in each instance in which it occurs. For example, if R^(i) and R^(j) are independently selected from the group consisting of methyl, ethyl, propyl and butyl, then (CR^(i)R^(j))₂ can be

In one embodiment of the invention, R^(a) is hydrogen or methyl. In a variant of this embodiment, R^(a) is hydrogen.

In one embodiment of the invention R⁴ is hydrogen or methyl. In a variant of this embodiment, R⁴ is hydrogen. In another embodiment R⁴ is methyl.

In one embodiment, p is 2 or 3.

In one embodiment, R³ and R⁷ are each independently selected from hydrogen, halogen, C₁₋₁₀ alkyl, and C₃₋₈cycloalkylC₀₋₁₀ alkyl.

In a further embodiment, R² and R⁷ are each independently selected from hydrogen, C₃₋₈ cycloalkylC₀₋₁₀ alkyl, and C₁₋₁₀ alkyl. In one embodiment of the invention, R³ and R⁷ are each independently selected from hydrogen, ethyl, propyl, butyl, pentyl, methyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In a variant of this embodiment, R³ and R⁷ are each independently selected from hydrogen, cyclopropyl, or methyl. In another variant, R³ is hydrogen.

In one embodiment A is selected from: furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, naphthyridinyl, benzothienyl, benzofuranyl, benzimidazole, benzpyrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolizinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, benzisoxazolyl, 5,6,7,8-tetrahydroquinolinyl, imidazo[1,2-c]pyridinyl, imidazo[1,2-c]pyrimidinyl, 5,6-dihydropyrrolo[1,2-b]pyrazolyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, thieno[2,3-b]pyrrolyl, furopyridinyl, thienopyridinyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dioxinyl, imidazo(2,1-b)(1,3)thiazole, and benzo-1,3-dioxolyl, phenyl, indenyl, and naphthyl.

In one embodiment, A is selected from phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, 2-3 dihydro-1H-isoindolyl, quinolinyl, isoquinolinyl, indolyl, and isoindolyl.

In one embodiment, A is selected from phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and 2-3 dihydro-1H-isoindolyl.

In one embodiment, X is selected from N and C. In another embodiment, X is selected from O and S.

In one embodiment, R^(5a) is selected from: halogen,

C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

C₁₋₁₀ heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

aryl C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

aryl C₂₋₁₀ alkynyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

(C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

C₁₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,

C₁₋₁₀ heteroalkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, ((C₀₋₁₀)alkyl)₁₋₂aminocarbonyloxy,

(C₀₋₁₀)heteroalkylaminocarbonyloxy, C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

(C₀₋₁₀)heteroalkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

C₃₋₈ cycloalkyl C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

aryl C₀₋₁₀alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

heteroarylC₀₋₁₀alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

(C₃₋₈)heterocycloalkylC₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl,

C₁₋₁₀ heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl, —CO₂(C₀₋₁₀ alkyl),

—(C₀₋₁₀ alkyl)CO₂H, Oxo (═O); C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl,

(C₃₋₈) cycloalkylsulfonyl, (C₃₋₈) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, —SO₂N(C₁₋₆alkyl)₁₋₂, —SO₂C₁₋₆alkyl, —SO₂CF₃, —SO₂CF₂H, —Si(CH₃)₃, (C₀₋₁₀ alkyl)₁₋₂ amino, hydroxy, (C₁₋₁₀ alkyl)OH, C₀₋₁₀ alkylalkoxy, cyano, (C₁₋₆alkyl)cyano, and C₁₋₆haloalkyl; wherein two R^(5a) and the atom to which they are attached may optionally form a −4, −5, or −6 member saturated ring system and wherein R^(5a) is each optionally substituted with 1, 2, 3, or 4 R⁶ substituents.

In another embodiment, R^(5a) is selected from: halogen, C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₂₋₁₀ alkynyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, (C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, (C₀₋₁₀)heteroalkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, C₃₋₈cycloalkyl C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, aryl C₀₋₁₀alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, heteroarylC₀₋₁₀alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, (C₃₋₈)heterocycloalkylC₀₋₁₀alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, —(C₀₋₁₀ alkyl)CO₂H, Oxo (═O); C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, (C₃₋₈) cycloalkylsulfonyl, (C₃₋₈) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, —SO₂N(C₁₋₆alkyl)₁₋₂, —SO₂C₁₋₆alkyl, —SO₂CF₃, —SO₂CF₂H, (C₀₋₁₀ alkyl)₁₋₂ amino, hydroxy, (C₁₋₁₀ alkyl)OH, C₀₋₁₀ alkylalkoxy, cyano, (C₁₋₆alkyl)cyano, and C₁₋₆haloalkyl; wherein two R^(5a) and the atom to which they are attached may optionally form a −4, −5, or −6 member saturated and wherein R^(5a) is each optionally substituted with 1, 2, 3, or 4 R⁶ substituents

In one embodiment, R^(5a) is independently selected from: tert-butyloxycarbonyl, fluoro, ethoxy, methoxy, methylsulfonyl, oxo, methoxycarbonyl, (methylamino)carbonyl, cyano, 2-hydroxypropanyl, hydroxyethyl, acetyl, methylcarbonyl, trifluoromethylcabonyl, methyl, pyrazolyl, amino, (trifluoromethyl)sulfonyl, (difluoromethyl)sulfonyl, hydroxymethyl, sulfamoyl, dimethylsulfamoyl, dimethylaminocarbonyl, trifluoromethyl, morpholinylcarbonyl, aminocarbonyl, chloro, 1,2,4-oxadiazolyl, cyclobutyloxy, ethoxycarbonyl, cyclopropyl, hydroxypropanyl, trifluoroethyl, bromo, methoxyoxoethyl, morpholinyl, isoxazolyl, phenyl, naphthalenyl, methylCOOH, trifluoroethyl, pyridinylmethyl, benzyl, cyanopropyl, napthalenylmethyl, cyclohexylmethyl, 1,3-benzodioxolylmethyl, propyl, methylsulfonyl, (2E)-3-phenylprop-2-enyl, benzofuranylmethyl, phenylprop-2-ynyl, imidazolylmethyl, pyrazolylmethyl, imidazo[I,2-a]pyridinylmethyl, pyrazinylmethyl, thiazoylmethyl, 1,3-thiazoylmethyl, tetrahydro-2H-pyranylmethyl, pyrazolo[1,5-a]pyridinylmethyl, pyrrolo[2,3-b]pyridinylmethyl, furanylmethyl, indolylmethyl, cyclobutylmethyl, 1,3-oxazolylmethyl, isoxazolymethyl, benzimidazolylmethyl, 4,5-dyhydroisoxazolylmethyl, phenylethyl, 1-phenylethyl, 2-fluoroethyl, methylsulfonyl, benzyloxycarbonyl, propyloxycarbonyl, cyclobutyloxycarbonyl, cyclobutylmethyloxycarbonyl, isopropyloxycarbonyl, tetrahydrofuranyloxycarbonyl, tetrahydropyranyloxycarbonyl, oxetanyloxycarbonyl, oxetanylmethyloxycarbonyl, propyloxycarbonyl, cyclopentyloxycarbonyl, cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, 2,3-dihydro-1H-indenyloxycarbonyl, pyridinylmethyloxycarbonyl, morpholinylethyloxycarbonyl, piperidinyloxycarbonyl, piperazinylethyloxycarbonyl, piperidinylmethyloxycarbonyl, ethyloxycarbonyl, cyclopropylmethyloxycarbonyl, naphthalenylethyloxycarbonyl, phenylethyloxycarbonyl, ethyloxycarbonyl, pyrrolidinylethyloxycarbonyl, pyridinylethyloxycarbonyl, pyridinylpropyloxycarbonyl, cyclopropylethyloxycarbonyl, ethylcarbonyl, (2E)-prop-2-enylcarbonyl methylcarbonyl, tert-butylcarbonyl, butylcarbonyl, methylcarbonyl, tetrahydrofuranylcarbonyl, pyridinylcarbonyl, pyrazinylcarbonyl, isoxazolylcarbonyl, cyclohexylcarbonyl, thiophenylcarbonyl, pyrrolidinylmethylcarbonyl, (1E)-ethylenylcarbonyl, phenylcarbonyl, indolylcarbonyl, benzylcarbonyl, naphthalenylcarbonyl, quinolinylcarbonyl, methylcarbonyl, tetrahydrofuranylmethylcarbonyl, methylethylcarbonyl, pyrazolylcarbonyl, cyclobutylcarbonyl, dimethylpropylcarbonyl, isopropylsulfonyl, furanylsulfonyl, tert-butylsulfonyl, phenylsulfonyl, imidazolylsulfonyl, cyclopropylsulfonyl, naphthalenylsulfonyl, trifluoromethylsulfonyl, phenylaminocarbonyl, cyclohexylaminocarbonyl, methylethylaminocarbonyl, butylaminocarbonyl, ethylaminocarbonyl, (1,1,3,3,-tetramethylbutyl)aminocarbonyl, phenylethylaminocarbonyl, azetidinyl, cyclohexylamino; phenylamino, pyridinylamino, tetrahydro-2H-pyranylamino, difluoromethylsulfonyl, ethylamino, cyclopropylmethylamino, methylamino, benzylamino, amino, tert-butylcarbonyl, 1,2,3,-tiazolyl, and tetrahydrofuranyloxycarbonyl; wherein two R^(5a) and the atom to which they are attached may optionally form a −4, −5, or −6 member saturated and wherein R^(5a) is each optionally substituted with 1, 2, 3, or 4 R⁶ substituents.

In one embodiment, R⁶ is independently selected from: halogen, C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀alkyl, aryl C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₂₋₁₀ alkynyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, (C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, C₂₋₁₀ alkenyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, ((C₀₋₁₀)alkyl)₁₋₂aminocarbonyloxy, C₁₋₁₀ alkylamino(oxy)₀₋₁ carbonylC₀₋₁₀ alkyl, C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl, —CO₂(C₀₋₁₀ alkyl), (C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl, —(C₀₋₁₀ alkyl)CO₂H, Oxo (═O), Sulfonyl, C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, (C₃₋₈)cycloalkylsulfonyl, (C₃₋₈)cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, —SO₂N(C₁₋₆alkyl)₁₋₂, —SO₂C₁₋₆alkyl, —SO₂CF₃, —SO₂CF₂H, C₁₋₁₀ alkylsulfinyl, amino, (C₀₋₁₀ alkyl)₁₋₂ amino, -(oxy)₀₋₁(carbonyl)₀₋₁N(C₀₋₁₀ alkyl)₁₋₂ C₁₋₄acylaminoC₀₋₁₀ alkyl, —Si(CH₃)₃, hydroxy, (C₁₋₁₀ alkyl)OH, C₁₋₁₀ alkoxy, cyano, and C₁₋₆ haloalkyl; wherein two R⁶ and the atoms to which they are attached may optionally form a 3-, 4-, 5-, or 6-membered saturated ring system and R⁶ is optionally substituted with 1, 2, or 3 substituents selected from hydrogen, hydroxy, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₁₋₁₀ alkyl)OH, halogen, CO₂H, —(C₀₋₆)alkylCN, —O(C═O)C₁-C₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy, trifluoromethyl, trifluoroethyl, —N—C(O)O(C₀₋₆)alkyl, C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, oxo (O═), (C₃₋₈) cycloalkylsulfonyl, (C₃₋₈) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, —SO₂N(C₁₋₆alkyl)₁₋₂, —SO₂C₁₋₆alkyl, —SO₂CF₃, —SO₂CF₂H, —C₁₋₁₀ alkylsulfinyl, —OSi(C₁₋₁₀alkyl)₃, —O₍₀₋₁₎(C₁₋₁₀)haloalkyl, amino(C₁₋₆alkyl)₀₋₂ and NH₂.

In another embodiment of the invention R⁶ is independently selected from:

halogen, C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

C₁₋₁₀ heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

(C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,

C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl,

C₁₋₁₀ alkyl(oxy)₀₋₁carbonylaminoC₀₋₁₀ alkyl, Oxo (═O), sulfonyl, arylsulfonyl, aminosulfonyl,

—SO₂C₁₋₆alkyl, —SO₂CF₃, —SO₂CF₂H, —Si(CH₃)₃, (C₀₋₁₀ alkyl)₁₋₂ amino, hydroxy,

C₁₋₁₀ alkoxy, (C₁₋₁₀ alkyl)cyano, cyano, and C₁₋₆haloalkyl; wherein two R⁶ and the atoms to which they are attached may optionally form a 3-, 4-, 5-, or 6-membered saturated ring system, and R⁶ is optionally substituted with 1, 2, or 3 substituents selected from hydrogen, hydroxy, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₁₋₁₀ alkyl)OH, halogen, CO₂H, —(C₀₋₆)alkylCN, —O(C═O)C₁-C₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy, trifluoromethyl, trifluoroethyl, —N—C(O)O(C₀₋₆)alkyl, C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, oxo (O═), (C₃₋₈) cycloalkylsulfonyl, (C₃₋₈) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, —SO₂N(C₁₋₆alkyl)₁₋₂, —SO₂C₁₋₆alkyl, —SO₂CF₃, —SO₂CF₂H, —C₁₋₁₀ alkylsulfinyl, —OSi(C₁₋₁₀alkyl)₃, —O₍₀₋₁₎(C₁₋₁₀)haloalkyl, amino(C₁₋₆alkyl)₀₋₂ and NH₂.

In one particular embodiment, R⁶ is independently selected from: oxo, tert-butyloxycarbonyl, methoxy, methyl, 1-hydroxymethylethyl, trifluoromethyl, fluoro, hydroxy, trifluoroethyl, ethoxy, methylethoxy, cyano, methoxycarbonyl, chloro, hydroxymethyl, trimethylsilyl, trimethylsilyloxy, difluoromethyl, ethoxycarbonyl, dimethylamino, methylcarbonyl, acetylamino, propyl, isopropyl, pyridinyl, morpholinyl, phenyl, piperazinyl, methylsulfonyl, ethyl, acetyl, difluoromethylsulfonyl, methylsulfonyl, phenylsulfonyl, methylcarbonylamino, and R⁶ is optionally substituted with 1, 2, or 3 substituents selected from hydrogen, hydroxy, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₁₋₁₀ alkyl)OH, halogen, CO₂H, —(C₀₋₆)alkylCN, —O(C═O)C₁-C₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy, trifluoromethyl, trifluoroethyl, —N—C(O)O(C₀₋₆)alkyl, C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, oxo (O═), (C₃₋₈) cycloalkylsulfonyl, (C₃₋₈) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, —SO₂N(C₁₋₆ alkyl)₁₋₂, —SO₂C₁₋₆ alkyl, —SO₂CF₃, —SO₂CF₂H, —C₁₋₁₀ alkylsulfinyl, —OSi(C₁₋₁₀alkyl)₃, —O₍₀₋₁₎(C₁₋₁₀)haloalkyl, amino(C₁₋₆alkyl)₀₋₂ and NH₂.

In one embodiment, R⁶ is optionally substituted with 1, 2, or 3 substituents selected from hydrogen, methyl, fluoro, trifluoromethyl, hydroxymethyl, oxo, hydroxy, and methoxy.

In one embodiment, the compounds of the instant invention are selective JAK1 inhibitors relative to JAK2. The determination of relative selectivity for a given compound of JAK1 inhibition is defined as the relative ratio of the (JAK2 IC₅₀ value/JAK1 IC₅₀ value) is at least 2. In yet another embodiment, for a given compound, the relative ratios of the (JAK2 IC₅₀ value/JAK1 IC₅₀ value) is at least 5.

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Therapeutically effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

The term “treatment” or “treating” includes alleviating, ameliorating, relieving or otherwise reducing the signs and symptoms associated with a disease or disorder.

The term “composition”, as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of formula I, and pharmaceutically acceptable excipients.

The term “optionally substituted” means “unsubstituted or substituted,” and therefore, the generic structural formulas described herein encompasses compounds containing the specified optional substituent as well as compounds that do not contain the optional substituent.

Each variable is independently defined each time it occurs within the generic structural formula definitions. For example, when there is more than one substituent for aryl/heteroaryl, each substituent is independently selected at each occurrence, and each substituent can be the same or different from the other(s). As another example, for the group —(CR³R³)₂—, each occurrence of the two R³ groups may be the same or different. As used herein, unless explicitly stated to the contrary, each reference to a specific compound of the present invention or a generic formula of compounds of the present invention is intended to include the compound(s) as well as pharmaceutically acceptable salts thereof.

Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

Compounds of formula I contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of formula I, either as single species or mixtures thereof.

Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of formula I.

Specific embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain one or more asymmetric centers and can thus occur as “stereoisomers” including racemates and racemic mixtures, enantiomeric mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. When bonds to the chiral carbon are depicted as straight lines in the Formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the Formula. For example, Formula I shows the structure of the class of compounds without specific stereochemistry. When the compounds of the present invention contain one chiral center, the term “stereoisomer” includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as racemic mixtures.

The compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

In the present application when a particular stereomeric compound is named using an “and” in the stereomeric designation, for example, 1-(2S,3S and 2R,3R)-3-cyclobutan-2-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide, the “and” indicates a racemic mixture of the enantiomers. That is, the individual enantiomers were not individually isolated.

When the stereomeric nomenclature includes “or”, for example, 1-(2S,3S or 2R,3R)-3-cyclobutan-2-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide, the “or” indicates that chiral resolution of racemate into individual enantiomers was accomplished but the actual optical activity of the specific enantiomer was not determined.

The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

Salts

The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

It will be understood that, unless otherwise specified, references to the compound of formula I, Ia, Ib, Ic, Id and Ie, subsets thereof, embodiments thereof, as well as specific compounds are meant to also include the pharmaceutically acceptable salts.

Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such all forms are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water (hydrates) or common organic solvents. Such solvates are encompassed within the scope of this invention.

Labelled Compounds

In the compounds of generic Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium (¹H) and deuterium (²H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.

Utilities

Compound of formula I or its pharmaceutically acceptable salts and pharmaceutical compositions can be used to treat or prevent a variety of conditions or diseases mediated by Janus kinases, in particular diseases or conditions that can be ameliorated by the inhibition of a Janus kinase such as JAK1, JAK2, JAK3 or TYK2. Such conditions and diseases include, but are not limited to:

(1) arthritis, including rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis; (2) asthma and other obstructive airways diseases, including chronic asthma, late asthma, airway hyper-responsiveness, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, recurrent airway obstruction, and chronic obstruction pulmonary disease including emphysema; (3) autoimmune diseases or disorders, including those designated as single organ or single cell-type autoimmune disorders, for example Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy, those designated as involving systemic autoimmune disorder, for example systemic lupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid, and additional autoimmune diseases, which can be B-cell (humoral) based or T-cell based, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, Type I or juvenile onset diabetes, and thyroiditis; (4) cancers or tumors, including alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast and mammary cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, including acute myelogenous leukemia and chronic myelogenous leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi's sarcoma, myelomas including multiple myeloma, myeloproliferative disorders, proliferative diabetic retinopathy, and angiogenic-associated disorders including solid tumors; (5) diabetes, including Type I diabetes and complications from diabetes; (6) eye diseases, disorders or conditions including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitis associated with Behcet's disease and lens-induced uveitis, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, and ocular neovascularization; (7) intestinal inflammations, allergies or conditions including Crohn's disease and/or ulcerative colitis, inflammatory bowel disease, coeliac diseases, proctitis, eosinophilic gastroenteritis, and mastocytosis; (8) neurodegenerative diseases including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, or neurodegenerative disease caused by traumatic injury, strike, glutamate neurotoxicity or hypoxia; ischemic/reperfusion injury in stroke, myocardial ischemica, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia, and platelet aggregation; (9) skin diseases, conditions or disorders including atopic dermatitis, eczema, psoriasis, scleroderma, pruritus and other pruritic conditions; (10) allergic reactions including anaphylaxis, allergic rhinitis, allergic dermatitis, allergic urticaria, angioedema, allergic asthma, or allergic reaction to insect bites, food, drugs, or pollen; (11) transplant rejection, including pancreas islet transplant rejection, bone marrow transplant rejection, graft-versus-host disease, organ and cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea, and xeno transplantation.

Accordingly, another aspect of the present invention provides a method for the treatment or prevention of a JAK-mediated disease or disorder comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I. In one embodiment such diseases include asthma and rheumatoid arthritis.

Another aspect of the present invention provides for the use of a compound of formula I in the manufacture of a medicament for the treatment or prevention of a JAK-mediated diseases or disorder.

One aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt or a stereoisomer thereof in the manufacture of a medicament for the treatment of a disease or a disorder ameliorated by the selective inhibition of a Janus kinase JAK1 relative to JAK 2.

Another aspect of the invention is the use of a compound of Formula I or a pharmaceutically acceptable salt or a stereoisomer thereof and a second active agent in the manufacture of a medicament for the treatment of a disease or a disorder ameliorated by the selective inhibition of a Janus kinase JAK1 relative to JAK 2.

Dose Ranges

The magnitude of prophylactic or therapeutic dose of a compound of formula I will, of course, vary with the nature and the severity of the condition to be treated and with the particular compound of formula I and its route of administration. It will also vary according to a variety of factors including the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and response of the individual patient. In general, the daily dose from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg. On the other hand, it may be necessary to use dosages outside these limits in some cases.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.05 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 99.95 percent of the total composition. Dosage unit forms will generally contain between from about 0.1 mg to about 0.4 g of an active ingredient, typically 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, or 400 mg.

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceutical compositions comprising a compound of formula I with a pharmaceutically acceptable carrier. For the treatment of any of the prostanoid mediated diseases compounds of formula I may be administered orally, by inhalation spray, topically, parenterally or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compound of the invention is effective in the treatment of humans.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and U.S. Pat. No. 4,265,874 to form osmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water-miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Dosage forms for inhaled administration may conveniently be formulated as aerosols or dry powders. For compositions suitable and/or adapted for inhaled administration, it is preferred that the active substance is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronization.

In one embodiment the medicinal preparation is adapted for use with a pressurized metered dose inhaler (pMDI) which releases a metered dose of medicine upon each actuation. The formulation for pMDIs can be in the form of solutions or suspensions in halogenated hydrocarbon propellants. The type of propellant being used in pMDIs is being shifted to hydrofluoroalkanes (HFAs), also known as hydrofluorocarbons (HFCs). In particular, 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) are used in several currently marketed pharmaceutical inhalation products. The composition may include other pharmaceutically acceptable excipients for inhalation use such as ethanol, oleic acid, polyvinylpyrrolidone and the like.

Pressurized MDIs typically have two components. Firstly, there is a canister component in which the drug particles are stored under pressure in a suspension or solution form. Secondly, there is a receptacle component used to hold and actuate the canister. Typically, a canister will contain multiple doses of the formulation, although it is possible to have single dose canisters as well. The canister component typically includes a valve outlet from which the contents of the canister can be discharged. Aerosol medication is dispensed from the pMDI by applying a force on the canister component to push it into the receptacle component thereby opening the valve outlet and causing the medication particles to be conveyed from the valve outlet through the receptacle component and discharged from an outlet of the receptacle. Upon discharge from the canister, the medication particles are “atomized”, forming an aerosol. It is intended that the patient coordinate the discharge of aerosolized medication with his or her inhalation, so that the medication particles are entrained in the patient's aspiratory flow and conveyed to the lungs. Typically, pMDIs use propellants to pressurize the contents of the canister and to propel the medication particles out of the outlet of the receptacle component. In pMDIs, the formulation is provided in a liquid or suspension form, and resides within the container along with the propellant. The propellant can take a variety of forms. For example, the propellant can comprise a compressed gas or liquefied gas.

In another embodiment the medicinal preparation is adapted for use with a dry powder inhaler (DPI). The inhalation composition suitable for use in DPIs typically comprises particles of the active ingredient and particles of a pharmaceutically acceptable carrier. The particle size of the active material may vary from about 0.1 μm to about 10 μm; however, for effective delivery to the distal lung, at least 95 percent of the active agent particles are 5 μm or smaller. Each of the active agent can be present in a concentration of 0.01-99%. Typically however, each of the active agents is present in a concentration of about 0.05 to 50%, more typically about 0.2-20% of the total weight of the composition.

As noted above, in addition to the active ingredients, the inhalable powder preferably includes pharmaceutically acceptable carrier, which may be composed of any pharmacologically inert material or combination of materials which is acceptable for inhalation. Advantageously, the carrier particles are composed of one or more crystalline sugars; the carrier particles may be composed of one or more sugar alcohols or polyols. Preferably, the carrier particles are particles of dextrose or lactose, especially lactose. In embodiments of the present invention which utilize conventional dry powder inhalers, such as the Handihaler, Rotohaler, Dislchaler, Twisthaler and Turbohaler, the particle size of the carrier particles may range from about 10 microns to about 1000 microns. In certain of these embodiments, the particle size of the carrier particles may range from about 20 microns to about 120 microns. In certain other embodiments, the size of at least 90% by weight of the carrier particles is less than 1000 microns and preferably lies between 60 microns and 1000 microns. The relatively large size of these carrier particles gives good flow and entrainment characteristics. Where present, the amount of carrier particles will generally be up to 95%, for example, up to 90%, advantageously up to 80% and preferably up to 50% by weight based on the total weight of the powder. The amount of any fine excipient material, if present, may be up to 50% and advantageously up to 30%, especially up to 20%, by weight, based on the total weight of the powder. The powder may optionally contain a performance modifier such as L-leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate.

Compounds of formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound of formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

Combinations with Other Drugs

For the treatment and prevention of JAK mediated diseases, compound of formula I may be co-administered with other therapeutic agents. Thus in another aspect the present invention provides pharmaceutical compositions for treating JAK mediated diseases comprising a therapeutically effective amount of a compound of formula I and one or more other therapeutic agents. In particular, for the treatment of the inflammatory diseases rheumatoid arthritis, psoriasis, inflammatory bowel disease, COPD, asthma and allergic rhinitis a compound of formula I may be combined with agents such as: (1) TNF-α inhibitors such as Remicade® and Enbrel®); (2) non-selective COX-I/COX-2 inhibitors (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); (3) COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib and etoricoxib); (4) other agents for treatment of rheumatoid arthritis including low dose methotrexate, lefunomide, ciclesonide, hydroxychloroquine, d-penicillamine, auranofin or parenteral or oral gold; (5) leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as zileuton; (6) LTD4 receptor antagonist such as zafirlukast, montelukast and pranlukast; (7) PDE4 inhibitor such as roflumilast; (8) antihistaminic H1 receptor antagonists such as cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine; (9) α1- and α2-adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride; (10) anticholinergic agents such as ipratropium bromide, tiotropium bromide, oxitropium bromide, aclindinium bromide, glycopyrrolate, pirenzepine, and telenzepine; (11) β-adrenoceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol, or methylxanthanines including theophylline and aminophylline, sodium cromoglycate; (12) insulin-like growth factor type I (IGF-1) mimetic; (13) inhaled glucocorticoid with reduced systemic side effects, such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide and mometasone furoate.

METHODS OF SYNTHESIS Schemes and Examples

The abbreviations used herein have the following tabulated meanings. Abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise.

ACN acetonitrile MeCN acetonitrile BAST bis(2-methoxyethyl)aminosulfur trifluoride Chiral SFC chiral super critical fluid chromatography CO₂ carbon dioxide Cs₂CO₃ cesium carbonate DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DCM dichloromethane DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DSC N,N-disuccinimidyl carbonate EDC 3-(ethyliminomethyleneamino)-N,N-dimethyl- propan-1-amine EtOAc ethyl acetate HATU O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate HCl hydrogen chloride HOBt 1-hydroxybenzotriazole HPLC high pressure liquid chromatography IPA 2-propanol LDA lithium diisopropylamide m-CPBA meta-chloroperoxybenzoic acid LRMS low resolution mass spectrometry MeI iodomethane Me—THF 2-methyltetrahydrofuran MgSO4 magnesium sulfate MP-(OAc)₃BH solid supported (macro porous) triacetoxyborohydride MPLC medium pressure liquid chromatography NaH sodium hydride Na₂SO₄ sodium sulfate NaBH4 sodium borohydride NaHCO₃ sodium bicarbonate NaOMe sodium methoxide Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0) POCl₃ phosphorus (V) oxychloride PyBOP (7-azabenzotriazol-1-yloxy)tripyrrolidino- phosphonium hexafluorophosphate SEM—Cl 2-(trimethylsilyl)ethoxymethyl chloride SiliaCat ® DPP—Pd silica bound diphenylphosphine palladium (II) TBAF tetra-n-butylammonium fluoride TBS—Cl tert-butyldimethylsilyl chloride t-BuOH tert-butanol TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran X-Phos 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl Me₄—^(t)Bu—X-Phos di-tert-butyl[3,4,5,6-tetramethyl-2′,4′,6′- tri(propan-2-yl)biphenyl-2-yl]phosphane NMO 4-methylmorpholine N-oxide TPAP tetra-n-propylammonium perruthenate (VII) HCOOH formic acid K^(t)OBu potassium tert-butoxide Na₂S₂O₅ sodium metabisulfite NMR nuclear magnetic resonance TLC thin layer chromatography (EtO)₂P(O)CH₂CN diethyl (cyanomethyl)phosphonate MsCl methanesulfonyl chloride TsOH p-toluenesulfonic acid KCN potassium cyanide Si—DMT silica supported Dimercaptotriazine TMS trimethylsilane CF₃TMS (trifluoromethyl)trimethylsilane Alkyl Group Abbreviations

Me methyl Et ethyl n-Pr normal propyl i-Pr isopropyl n-Bu normal butyl i-Bu isobutyl s-Bu secondary butyl t-Bu tertiary butyl c-Pr cyclopropyl c-Bu cyclobutyl c-Pen cyclopentyl c-Hex cyclohexyl

METHODS OF SYNTHESIS

The compounds of the present invention can be prepared according to the following general schemes using appropriate materials, and are further exemplified by the subsequent specific examples. The compounds illustrated in the examples are not to be construed as forming the only genus that is considered as the invention. The illustrative Examples below, therefore, are not limited by the compounds listed or by any particular substituents employed for illustrative purposes. Substituent numbering as shown in the schemes does not necessarily correlate to that used in the claims and often, for clarity, a single substituent is shown attached to the compound where multiple substituents are allowed under the definitions of the instant invention herein above.

Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:

All reactions were stirred (mechanically, stir bar/stir plate, or shaken) and conducted under an inert atmosphere of nitrogen or argon unless specifically stated otherwise.

All temperatures are degrees Celsius (° C.) unless otherwise noted.

Ambient temperature is 15-25° C.

Most compounds were purified by reverse-phase preparative HPLC, MPLC on silica gel, recrystallization and/or swish (suspension in a solvent followed by filtration of the solid).

The course of the reactions was followed by thin layer chromatography (TLC) and/or LCMS and/or NMR and reaction times are given for illustration only.

All end products were analyzed by NMR and LCMS.

Intermediates were analyzed by NMR and/or TLC and/or LCMS.

Method 1

General procedures to prepare intermediates of the instant invention are described in Scheme 1. Alkyl Grignard reagents are reacted with appropriately substituted (hetero)aryl carboxylates I at or around 0° C. in an appropriate solvent, such as THF, to afford intermediates II used in the synthesis of examples of the instant invention.

Method 2

General procedures to prepare intermediates of the instant invention are described in Scheme 2. A trifluoromethyl anion equivalent, such as CF₃TMS, is reacted with TBAF and an appropriately substituted (hetero)aryl aldehyde III in an appropriate solvent, such as THF, to yield intermediates IV used in the synthesis of examples of the instant invention.

Method 3

General procedures to prepare intermediates of the instant invention are described in Scheme 3. Heteroaryl boronate esters or boronic acids VI are cross coupled to optionally substituted (hetero)aryl bromides V using a suitable palladium complex, such as Pd(dppf)Cl₂, and an appropriate base, such as K₃PO₄, in a compatible solvent or solvent mixture, such as 10:1 v:v dioxane:water, at or around 90° C. to yield intermediates VII in the synthesis of examples of the instant invention.

Method 4

General procedures to prepare intermediates of the instant invention are described in Scheme 4. Appropriately substituted benzyl bromides VIII can be reacted with aza heterocycles using a suitable base, such as potassium acetate, or be reacted with sodium azide followed by optionally substituted acetylenes and standard “Click chemistry” reagents to afford intermediates IX in the synthesis of examples of the instant invention.

Method 5

General procedures to prepare intermediates of the instant invention are described in Scheme 5. Appropriately substituted benzyl bromides X can be reacted with methyl hydroxy acetate in the presence of a suitable base, such as sodium hydride, and then further reacted with alkyl Grignard reagents to afford intermediates XI in the synthesis of examples of the instant invention.

Method 6

General procedures to prepare intermediates of the instant invention are described in Scheme 6. Appropriately substituted thiophenols XII are reacted with a suitable base, such as sodium hydride, and a trifluoromethylating agent, such as 5-(trifluoromethyl)dibenzo[b,d]thiophenium trifluoromethanesulfonate at ambient temperature in an appropriate solvent, such as DMF. The resulting intermediate is oxidized to the corresponding sulfone XIII with a suitable oxidant, such as m-CPBA, to afford an intermediate used in the synthesis of examples of the instant invention.

Method 7

General procedures to prepare intermediates of the instant invention are described in Scheme 7. Appropriately substituted thiophenols XII are reacted with a suitable base, such as potassium hydroxide, and a difluoromethylating agent, such as diethyl[bromo(difluoro)methyl]phosphonate, in an appropriate solvent or solvent mixture, such as 1:1 v:v MeCN:water. The resulting intermediate is oxidized to the corresponding sulfone XIV with a suitable oxidant, such as m-CPBA, to afford an intermediate used in the synthesis of examples of the instant invention.

Method 8

General procedures to prepare intermediates of the instant invention are described in Scheme 8. Appropriately substituted aryl sulfoxides XV are reacted with a Lewis acid, such as zinc iodide, and a suitable nucleophilic fluorine source, such as BAST, in a solvent, such as 1,2-DCE, at or around 40° C. The resulting intermediate is oxidized to the corresponding sulfone XVI with a suitable oxidant, such as m-CPBA, to afford an intermediate used in the synthesis of examples of the instant invention.

Method 9

General procedures to prepare intermediates of the instant invention are described in Scheme 9. Appropriately substituted benzothiophenes XVII are oxidized to the corresponding sulfones with a suitable oxidant, such as m-CPBA, and then hydroxylated upon stirring in aqueous sodium hydroxide at or around 100° C. to afford intermediates XVIII in the synthesis of examples of the instant invention.

Method 10

General procedures to prepare intermediates of the instant invention are described in Scheme 10. Appropriately substituted 2,3-dihydro-1H-isoindol-ones XIX can be poly-methylated using a suitable base, such as sodium hydride, and methyl iodide to afford intermediates XX used in the synthesis of examples of the instant invention.

Method 11

General procedures to prepare intermediates of the instant invention are described in Scheme 11. Appropriately substituted 2,3-dihydro-1H-isoindol-ones XIX can be mono-alkylated using a suitable base, such as sodium hydride, and optionally substituted alkylating agents to afford intermediates XXI in the synthesis of examples of the instant invention.

Method 12

General procedures to prepare intermediates of the instant invention are described in Scheme 12. Optionally substituted alkyl aldehydes XXII are condensed with diethyl (cyanomethyl)phosphonate in the presence of a suitable base, such as potassium tert-butoxide to yield substituted acrylonitriles XXIII used as intermediates in the synthesis of examples of the instant invention.

Method 13

General procedures to prepare intermediates of the instant invention are described in Scheme 13. Optionally substituted carbamate protected heterocyclic ketones XXIV are condensed with diethyl (cyanomethyl)phosphonate in the presence of a suitable base, such as potassium tert-butoxide, to yield optionally substituted acrylonitriles XXV used as intermediates in the synthesis of examples of the instant invention.

Method 14

General procedures to prepare intermediates of the instant invention are described in Scheme 14. Carbamate protected optionally substituted acrylonitriles XXV are deprotected in the presence of a suitable acid, such as TFA or HCl, to form amino intermediates XXVI that are further derivatized to form sulfonamide XXVII, urethane XXVIII, and N-arylated intermediates XXIX. Sulfonamide derivatives XXVII are formed by reacting deprotected optionally substituted acrylonitriles with optionally substituted sulfoyl chlorides in a suitable solvent, such as DCM, using an appropriate base, such as DIPEA. Urea derivatives XXVIII are formed by reacting deprotected optionally substituted acrylonitriles with a doubly activated carbonyl equivalent, such as DSC, and optionally substituted alcohols in the presence of a suitable base, such as TEA. N-arylated derivatives XXIX are formed by reacting deprotected optionally substituted acrylonitriles with optionally substituted aryl halides using a suitable palladium-ligand system, such as Pd₂(dba)₃ and X-Phos, an appropriate base, such as Cs₂CO₃, in a solvent, such as t-BuOH, at or around 90° C.

Method 15

General procedures to prepare intermediates of the instant invention are described in Scheme 15. Cyanohydrins XXXI of optionally substituted (hetero)cyclic ketones XXX are prepared using aqueous sodium metabisulfite, followed by the addition of a suitable cyanide source, such as potassium cyanide. Hydroxyl group activation with a suitable agent, such as mesyl chloride or POCl₃, followed by elimination under appropriate conditions, such as refluxing pyridine, yields substituted acrylonitriles XXXII used as intermediates in the synthesis of examples of the instant invention.

Method 16

General procedures to prepare intermediates of the instant invention are described in Scheme 16. Optionally substituted (hetero)cyclic ketones XXXIII are enolized with an appropriate base, such as LDA, and reacted with a suitable triflating agent, such as N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide. The resulting vinyl triflate XXXIV is reacted with a suitable palladium complex, such as tetrakis(triphenylphosphine) palladium (0), and an appropriate cyanide source, such as zinc cyanide, to afford substituted acrylonitriles XXXV used as intermediates in the synthesis of examples of the instant invention.

Method 17

General procedures to prepare intermediates of the instant invention are described in Scheme 17. Acrylonitrile is made to under go a Diels-Alder cyclization with an appropriately substituted butadiene using standard conditions, such as refluxing benzene. The cycloaddition product is deprotected with aqueous acid, such as 1N HCl, to provide substituted cyclohexenone XXXVI, which is then reacted with a suitable reductant, such as cerium (III) chloride and sodium borohydride, to afford intermediates XXXVII used in the synthesis of examples of the instant invention.

Method 18

General procedures to prepare intermediates of the instant invention are described in Scheme 18. 2-Chloroprop-2-enenitrile is reacted with benzene sulfinic acid sodium salt in aqueous acetic acid. The resulting olefin is regenerated by eliminating the chloro substituent with an appropriate base, such as TEA. The obtained acrylonitrile XXXVIII is made to undergo a Diels-Alder cyclization with an appropriately substituted butadiene using standard conditions, such as refluxing benzene, to yield a cyano benzosulfone substituted cyclohexanone XXXIX. This substituted cyclohexanone XXXIX is protected with ethylene glycol under acidic conditions, such as TsOH, in an appropriate solvent, such as benzene, at elevated temperatures, e.g. at or around 110° C. The acetal substituted acrylonitrile XL is obtained after elimination of the benzosulfone with an appropriate base, such as potassium tert-butoxide. This synthetic sequence affords intermediates used in the synthesis of examples of the instant invention.

Method 19

General procedures to prepare intermediates of the instant invention are described in Scheme 19. 3-Amino pyrazole carboxamide XLI is cross coupled to (hetero)aryl halides XLII using a catalytic palladium-ligand system, such as Pd₂(dba)₃, and Me₄-^(t)Bu-X-Phos, with a suitable base, such as K₃PO₄ or KOAc, in an appropriate solvent, such as 2-propanol, to yield pyrazole intermediates XLIII.

Method 20

General procedures to prepare intermediates of the instant invention are described in Scheme 20. 3-Amino-1H-pyrazole-4-carbonitrile XLIV is reacted with a suitable base, such as sodium hydride, and SEM-Cl to yield a mixture of 3-amino pyrazoles XLV and XLVI, which are arylated with an appropriately substituted halogenated (hetero)aromatic XLII using a suitable catalytic palladium-ligand system, such as Pd₂(dba)₃ and X-Phos, an appropriate base, such as K₃PO₄, in a suitable solvent, such as dioxane. The intermediate nitriles XLVII and XLVIII are oxidized to the corresponding amides using an appropriate oxidant, such as hydrogen peroxide mixed with sodium hydroxide, and the SEM group is then removed by acid hydrolysis to yield pyrazole XLIII, an intermediate in the synthesis of examples of the instant invention.

Method 21

General procedures to prepare intermediates of the instant invention are described in Scheme 21. Using an appropriate base, such as DBU, in a suitable solvent, such as MeCN, EtOH, or tert-BuOH, 3-amino pyrazole carboxamide XLI is conjugatively added to optionally substituted acrylonitriles, including but not limited to those illustrated in Schemes #12-18 to yield alkylated pyrazole carboxamide XLIX, an intermediate in the synthesis of examples of the instant invention.

Method 22

General procedures to prepare examples of the instant invention are described in Scheme 22. Methyl 5-amino-1H-pyrazole-4-carboxylate L is conjugatively added to substituted acrylonitriles including but not limited to those illustrated in Schemes #12-18 in the presence of a suitable base, such as catalytic sodium methoxide. The resulting intermediates LI are cross coupled to (hetero)aryl halides XLII using an appropriate catalytic palladium-ligand system, such as Pd₂(dba)₃ and X-Phos, and an appropriate base, such as K₃PO₄. Saponification of LII using aqueous hydroxide, such as LiOH, followed by amide formation using standard conditions, such as EDC, HOBT, and optionally substituted primary and secondary amines yields examples LIV of the instant invention.

Method 23

General procedures to prepare examples of the instant invention are described in Scheme 23. Using an appropriate base, such as DBU, in a suitable solvent, such as MeCN, EtOH, or tert-BuOH, N-(hetero)arylated pyrazole carboxamides XLIII are conjugatively added to optionally substituted acrylonitriles, including but not limited to those illustrated in Schemes #12-18 to yield examples LV of the instant invention.

Method 24

General procedures to prepare examples of the instant invention are described in Scheme 24. Alkylated 3-amino pyrazole carboxamides XLIX are cross coupled to (hetero)aryl halides XLII using an appropriate catalytic palladium-ligand system, such as Pd₂(dba)₃ and X-Phos or Me₄ ^(t)Bu-X-Phos, and a suitable base, such as K₃PO₄ or KOAc, in solvent, such as dioxane, to yield examples LV of the instant invention.

Method 25

General procedures to prepare examples of the instant invention are described in Scheme 25. Using a solid supported palladium system, such as SiliaCat® DPP-Pd and a suitable base, such as, K₂CO₃, optionally substituted boronic acids LVII are cross coupled to bromophenyl substituted pyrazoles LVI to yield examples LVIII of the instant invention.

Method 26

General procedures to prepare examples of the instant invention are described in Scheme 26. Hydroxy substituted amino pyrazole carboxamides LIX can be fluorinated using a nucleophilic fluorine source, such as BAST, to afford examples LX of the instant invention.

Method 27

General procedures to prepare examples of the instant invention are described in Scheme 27. N-(hetero)arylated pyrazole carboxamides XLIII can be alkylated with optionally substituted alkyl halides LXI using heat and an appropriate base, such as Cs₂CO₃, to afford examples LXII of the instant invention.

Method 28

General procedures to prepare examples of the instant invention are described in Scheme 28. Carbamate protected substituted amino pyrazole carboxamides LXII are deprotected in the presence of acid, such as TFA or HCl, to provide amino intermediates LXIV which are further derivatized using standard conditions known by those skilled in the art to yield examples of the instant invention. Examples include but are not limited to alkylated LXV, reductively aminated LXVI, and arylated LXVII derivatives, as well as carbamates LXVIII, ureas LXIX, amides LXX, and sulfonamides LXXI.

Method 29

General procedures to prepare examples of the instant invention are described in Scheme 29. Hydroxylated cyclohexyl pyrazole carboxamides LIX can be oxidized with an appropriate oxidant, such as TPAP and NMO, and then reductively aminated using standard conditions, such as AcOH, NACNBH₃, and optionally substituted primary and secondary amines, to afford examples LXXIII of the instant invention.

Method 30

General procedures to prepare examples of the instant invention are described in Scheme 30. Hydroxylated cyclohexyl pyrazole carboxamides LIX can be reacted with optionally substituted isocyanates and DMAP to afford carbamate derivatives LXXIV of the instant invention.

Method 31

General procedures to prepare examples of the instant invention are described in Scheme 31. Optionally substituted, carbamate protected pyrazole carboxamides LXXV are deprotected in the presence of acid, such as TFA or HCl, and then reacted with optionally substituted alcohols in the presence of a doubly activated carbonyl group, such as DSC or phosgene, to afford carbamate derivatives LXXVII of the instant invention.

Method 32

Cyclic sulfide-containing ketones such as LXXVIII are condensed with diethyl (cyanomethyl)phosphonate in the presence of a suitable base, such as potassium tert-butoxide, to yield optionally substituted unsaturated nitriles LXXIX used as intermediates in the synthesis of examples of the instant invention. Using an appropriate base, such as DBU, in a suitable solvent, such as MeCN, EtOH, or tert-BuOH, 3-amino pyrazole carboxamide XLIII is conjugatively added to optionally substituted acrylonitriles, including but not limited to LXXIX to yield alkylated pyrazole carboxamides such as LXXX as examples of the instant invention.

Method 33

Cyclic sulfone-containing ketones such as LXXXI are condensed with diethyl (cyanomethyl)phosphonate in the presence of a suitable base, such as potassium tert-butoxide, to yield optionally substituted unsaturated nitriles LXXXII used as intermediates in the synthesis of examples of the instant invention. Using an appropriate base, such as DBU, in a suitable solvent, such as MeCN, EtOH, or tert-BuOH, 3-amino pyrazole carboxamide XLIII is conjugatively added to optionally substituted acrylonitriles, including but not limited to LXXXII to yield alkylated pyrazole carboxamides such as LXXXIII as examples of the instant invention.

Method 34

Ketal protected pyrazole derivatives such as LXXXIV are deprotected using standard conditions, such as but not limited to aqueous hydrochloric acid solution in tetrahydrofuran at elevated temperature to yield intermediate ketones such as LXXXV. Ketone derivatives such as LXXXV are then reductively aminated with ammonium chloride, primary amines, or secondary amines to yield amine-substituted intermediates of the general structure LXXXVI. These pyrazole intermediates are then cross-coupled with aryl halides such as, but not limited to XLII to yield amine-containing pyrazole carboxamides such as LXXXVII as examples of the instant invention.

Method 35

As an alternative to Method 34 in the preparation of amine-containing pyrazole examples, optionally substituted ketones such as LXXXVIII are reductively aminated with ammonium acetate, using sodium cyanoborohydride or another appropriate reagent to yield primary amines such as LXXXIX, which are both examples and intermediates for use in the instant invention. Aldehydes of diverse structure can then be coupled to primary amine LXXXIX with a reductive amination reaction, such as with sodium cyanoborohydride and acetic acid to afford secondary amines such as XC as examples of the instant invention.

Method 36

As an alternative in the preparation of amine containing examples of the instant invention, ketal protected pyrazole derivative LXXXIV can be cross-coupled to XLII using an appropriate catalytic palladium-ligand system, such as Pd₂(dba)₃ and X-Phos or Me₄ ^(t)Bu-X-Phos, and a suitable base, such as K₃PO₄ or KOAc, in solvent, such as dioxane, to yield arylated compounds such as XCI for use as intermediates in the instant invention. Arylated ketal derivatives such as XCI can then be deprotected using aqueous acidic conditions such as aqueous hydrochloric acid in tetrahydrofuran to give ketone derivatives such as LXXXVIII as intermediates which can then be reductively aminated with secondary or primary amines to give amine substituted compounds such as LXXXVII as examples of the instant invention.

Method 37

Piperidines such as XCII can be reductively aminated with optionally substituted aldehydes using an acid, such as trifluoroacetic acid or acetic acid, and a reducing reagent, such as sodium triacetoxy borohydride, to give tertiary amine substituted pyrazoles such as XCIII as examples of the instant invention.

Method 38

As an alternative to the preparation of tertiary amine containing examples, primary or secondary alcohols can be oxidized to the corresponding aldehydes or ketones with polystyrene-supported IBX, followed by reductive amination with secondary amines such as XCIV and appropriate reaction conditions, such as trifluoroacetic acid and sodium triacetoxyborohydride to give XCV as examples of the instant invention.

Method 39

Optionally substituted ketones such as LXXXVIII can be reduced with reagents such as sodium borohydride, the resulting alcohol can be activated as a leaving group with a reagent such as methanesulfonyl chloride, and the resulting mesylate or optionally activated alcohol derivative can be displaced with an azide source, such as sodium azide to give alkylated azide XCVI as intermediates for use in the instant invention. The azides can then be reacted with substituted alkynes in a 1,3-dipolar cycloaddition with copper II sulfate and sodium ascorbate in an appropriate solvent to afford triazole containing pyrazole carboxamides XCVII as examples of the instant invention.

Method 40

Using an appropriate base, such as DBU, in a suitable solvent, such as MeCN, EtOH, or tert-BuOH, 3-amino pyrazole carboxamide XLIII is conjugatively added to optionally substituted acrylonitriles, including but not limited to XCVIII to yield t-butyl ester substituted pyrazole carboxamides such as XCIX as intermediates for use in instant invention. The t-butyl esters such as XCIX can then be converted to carboxylic acids by treatment with trifluoroacetic acid (or another appropriate acid), and the carboxylic acid can be subjected to amide coupling conditions to give amide substituted pyrazole compounds such as C as examples of the instant invention.

COMMERCIALLY AVAILABLE/PREVIOUSLY DESCRIBED MATERIALS

The following table lists commercial sources, and previously disclosed synthetic routes for chemical materials employed in the synthesis of intermediates, and Examples of the instant invention. The list is not intended to be exhaustive, exclusive, or limiting in any way.

Structure Compound Name Vendor

4,4,4-trifluorobut-2-enenitrile Oakwood

4-bromo-N-methylbenzamide Combi Blocks, Inc.

3-hydroxycyclohex-1-ene-1-carbonitrile J. Org. Chem. 2001, 66, 2171- 2174.

6-hydroxycyclohex-1-ene-1-carbonitrile Tetrahedron Letters 1986, 27, 1577-1578.

5-hydroxycyclohex-1-ene-1-carbonitrile Canadian Journal of Chemistry 1984, 62, 1093-1098.

(5-bromo-2-mercaptophenyl)methanol Biogene Organics, Inc.

tert-butyl 4-cyano-4-hydroxypiperidine- 1-carboxylate Sinova, Inc.

3-amino-1H-pyrazole-4-carboxamide Enamine

5-(4-bromophenyl)-3-methyl-1,2,4- oxadiazole Maybridge

5-(4-bromophenyl)-1,3-oxazole Maybridge

2-(4-bromophenyl)-1H-imidazole J & W PharmLab LLC

3-(4-bromophenyl)-5-methyl-1,2,4- oxadiazole Maybridge

tert-butyl 5-bromo-1-oxo-1,3-dihydro- 2H-isoindole-2-carboxylate Ontario Chemical, Inc.

5-bromo-2,3-dihydro-1H-isoindol-1- one Atomole Scientific Co, ltd.

5-bromo-2-methyl-2,3-dihydro-1H- isoindol-1-one J & W PharmLab LLC

2,2,2-trifluoroethyl trifluoromethanesulfonate Matrix Scientific

3-oxocyclohexanecarboxylic acid Sigma Aldrich

methyl 4-oxocyclohexanecarboxylate Astatech Inc

3-bromobutyronitrile TCI America

3-hydroxy-2,2-dimethylpropanenitrile Matrix Scientific

1,1,1-trifluoro-2-propanol Sigma Aldrich

1,3-difluoro-2-propanol Sigma Aldrich

3-dimethylamino-2,2-dimethyl-1- propanol TCI America

2,2-difluoropropane-1,3-diol Chemstep

[1-(hydroxymethyl)cyclopropyl]- acetonitrile Matrix Scientific

oxetan-3-ol Sigma Aldrich

(3-methyloxetan-3-yl)methanol Sigma Aldrich

2-cyclopropylethanol Sigma Aldrich

Silica supported Dimercaptotriazine (Si—DMT) Silicycle Inc.

Silica supported Isocyanate Silicycle Inc.

4-bromo-2-fluoropyridine Synthonix

methyl 5-amino-1H-pyrazole-4- carboxylate Chembridge Corporation

5-bromo-2-fluoropyridine Matrix Scientific

4-bromopyridazine Fisher Scientific

4-bromo-N,N-dimethylbenzamide Chembridge Corporation

4-bromobenzenesulfonamide Sigma Aldrich

1-bromo-4- [(trifluoromethyl)sulfonyl]benzene Sunshine ChemLab. Inc

1-bromo-4- [(difluoromethyl)sulfonyl]benzene WXAT

5-bromopyridine-2-carbonitrile Sigma Aldrich

methyl (4-bromophenyl)acetate Toyobo Co., Ltd.

methyl 2-hydroxy-2-methylpropanoate Sigma Aldrich

tert-butyl 3-methyl-4-oxopiperidine-1- carboxylate Small Molecules Inc.

tert-butyl 2-methyl-4-oxopiperidine-1- carboxylate Small Molecules Inc.

4-bromo-2-(trifluoromethyl)pyridine CombiPhos Catalysts, Inc.

3-methylbut-2-enenitrile BePharm Ltd.

cyclobutanecarbaldehyde Beta Pharma Inc

tetrahydro-2H-pyran-3-carbaldehyde J & W PharmLab LLC

tetrahydro-2H-pyran-4-ylacetaldehyde Maybridge

tert-butyl 4-acetylpiperidine-1- carboxylate Syntech Development Company

tert-butyl 4-fluoro-4-formylpiperidine- 1-carboxylate Ark Pharm, Inc.

tert-butyl 4-oxocyclohexanecarboxylate Fisher Scientific

tert-butyl (4-oxocyclohexyl)carbamate Fisher Scientific

oxetan-3-one Synthonix

tetrahydro-4H-pyran-4-one Fisher Scientific

3-oxocyclobutanecarbonitrile Fisher Scientific

1,4-dioxaspiro[4.5]decan-8-one Sigma Aldrich

tert-butyl 6-oxo-2- azaspiro[3.3]heptane-2-carboxylate Org. Lett. 2009, 11, 3523-3525.

5-bromopyrimidine-2-carbonitrile Fisher Scientific

4-(5-BROMOPYRIDIN-2- YL)MORPHOLINE Fisher Scientific

INTERMEDIATES

The following experimental procedures detail the preparation of chemical materials used in the synthesis of Examples of the instant invention. The exemplified procedures are for illustrative purposes only, and are not intended to limit the scope f the instant invention in any way.

1-{[tert-Butyl(dimethyl)silyl]oxy}propan-2-ol

To a solution of propylene glycol (1.0 g, 13 mmol) in DCM (60.0 mL) was added tert-butyldimethylchlorosilane (2.0 g, 13 mmol) followed by DIPEA (3.2 mL, 18 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solution was diluted with ether, washed with saturated aqueous NaHCO₃, brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo to afford the title compound.

LRMS (ESI) calc'd for C₉H₂₂O₂Si [M+H]⁺: 191. Found: 191.

tert-Butyl 3-oxocyclohexanecarboxylate

Anhydrous MgSO₄ (3.4 g, 28 mmol) was suspended in DCM (28.1 mL) and to this vigorously stirred mixture was added concentrated sulfuric acid (0.7 g, 7 mmol). The resulting mixture was allowed to stir at ambient temperature for 30 minutes. 3-Oxocyclohexanecarboxylic acid (1.0 g, 7.0 mmol) was added followed by t-BuOH (2.6 g, 35 mmol). The resulting mixture was allowed to stir for 24 hours before it was filtered and flushed with DCM. The filtrate was washed with water, and the organic layer was again washed with water, brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo to afford the title compound. The residue was used without further purification.

¹H NMR (500 MHz, CDCl₃): δ 2.72-2.64 (m, 1H), 2.47 (d, J=8.1 Hz, 2H), 2.36-2.24 (m, 2H), 2.08-1.98 (m, 2H), 1.84-1.66 (m, 2H), 1.44 (s, 9H).

Methyl 3-oxocyclohexanecarboxylate

To a solution of 3-oxocyclohexanecarboxylic acid (1.0 g, 7.0 mmol) in diethyl ether (28 mL) was added dropwise TMS-diazomethane (3.5 mL, 7.0 mmol, 2.0 mL in diethyl ether). MeOH (30 mL) was added and the mixture was maintained at ambient temperature for 30 minutes. The mixture was concentrated in vacuo, and the residue was purified by MPLC on silica gel (using a gradient elution of 0-45% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.

¹H NMR (500 MHz, CDCl₃): δ 3.66 (s, 3H), 2.82-2.72 (m, 1H), 2.54-2.46 (m, 2H), 2.38-2.24 (m, 2H), 2.12-1.98 (m, 2H), 1.86-1.75 (m, 1H), 1.75-1.64 (m, 1H).

5-{[tert-Butyl(dimethyl)silyl]oxy}cyclohex-1-ene-1carbonitrile

5-Hydroxycyclohex-1-ene-1-carbonitrile (500 mg, 4.06 mmol) was dissolved in anhydrous DMF (5.1 mL) and then cooled to 0° C. Imidazole (276 mg, 4.06 mmol) and TBS-Cl (612 mg, 4.06 mmol) were added and the reaction mixture was allowed to stir at 0° C. for 2 hours. The reaction mixture was partitioned between water and DCM. The organic layer was collected and the aqueous layer was again extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-100%, EtOAc/hexanes) to afford the title compound.

LRMS (ESI) calc'd for C₁₃H₂₃NOSi [M+H]⁺: 238. Found: 238.

2-(5-Bromopyridin-2-yl)propan-2-ol

Methyl 5-bromopicolinate (500 mg, 2.31 mmol) was dissolved in THF (7.0 mL) and the flask was sealed with a septum and flushed with argon. The mixture was cooled to 0° C. and methylmagnesium bromide (3.1 mL, 9.3 mmol, 3M in THF) was added. The resulting mixture was allowed to stir at 0° C. for 1 hour before the reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was then washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo to afford the title compound, which was used without further purification. LRMS (ESI) calc'd for C₈H₁₀BrNO [M+H]⁺: 216. Found: 216.

1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethanol

5-Bromopicolinaldehyde (500 mg, 2.70 mmol) was dissolved in THF (9.0 mL) and the flask was then sealed with a septum, flushed with argon, and cooled to 0° C. (Trifluoromethyl)trimethylsilane (0.44 mL, 3.0 mmol) was then added followed by TBAF (2.7 mL, 2.7 mmol, 1M in THF). The resulting mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The reaction was then quenched with water and extracted with DCM (2×). The combined organic extracts were washed with brine, dried over anhydrous MgSO₄, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 10-20% EtOAc/hexanes) to afford the title compound. LRMS (ESI) calc'd for C₈H₆BrF₃O [M+H]⁺: 256. Found: 256.

4-(3-Bromophenyl)-1-methyl-1H-pyrazole

1,3-Dibromobenzene (0.38 mL, 3.2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (595 mg, 2.86 mmol), Pd(dppf)Cl₂ (260 mg, 0.320 mmol), and potassium phosphate (2.0 g, 9.5 mmol) were combined in a flask and dissolved in dioxane (16.0 mL) and water (1.6 mL). The flask was then sealed and flushed with argon. The reaction mixture was allowed to stir at 90° C. for 90 minutes. The mixture was then cooled to ambient temperature and diluted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO₄, and concentrated in vacuo. The residue was purified by MPLC on silica gel (50% EtOAc/hexanes) to afford the title compound.

LRMS (ESI) calc'd for C₁₀H₉BrN₂ [M+H]⁺: 237. Found: 237.

The following intermediates found in TABLE 1 were prepared according to Scheme #3 following similar procedures described for Intermediate #7-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 1 Exact Compound Mass Intermediate Structure Name [M + H]⁺ 7-2

3-bromo-5- (1-methyl-1H- pyrazol-4-yl) pyridine Calc'd 238, Found 238

1-(3-Bromobenzyl)-1H-benzotriazole

To a solution of 1H-benzotriazole (0.52 g, 4.4 mmol) in THF (25 mL) was added potassium tert-butoxide (4.6 mL, 4.6 mmol, 1M in THF) followed by the addition of 1-bromo-3-(bromomethyl)benzene (1.0 g, 4.0 mmol). The solution was allowed to stir for 4 hours before the reaction was quenched with saturated aqueous NaHCO₃ and diluted with EtOAc. The organic layer was separated and washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated to dryness in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-80% EtOAc/hexanes) to afford the title compound as a white solid.

LRMS (ESI) calc'd for C₁₃H₁₁BrN₃ [M+H]⁺: 288. Found 288.

The following intermediates disclosed in TABLE 2 were prepared according to Scheme #4 following similar procedures described for Intermediate #8-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 2 Exact Compound Mass Intermediate Structure Name [M + H]⁺ 8-2

1-(3-bromo- benzyl)-1H- imidazole Calc'd 237, Found 237

{5-Bromo-2-[(trifluoromethyl)sulfanyl]phenyl}methanol

NaH (120 mg, 3.01 mmol, 60% dispersion in oil) and 5-(trifluoromethyl)dibenzo[b,d]thiophenium trifluoromethanesulfonate (808 mg, 2.01 mmol) were added sequentially to a solution of (5-bromo-2-sulfanylphenyl)methanol (440 mg, 2.01 mmol) in DMF (10 mL) at 23° C. The reaction mixture was stirred at 23° C. for 45 minutes, and was then partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20%, EtOAc/hexanes) to afford the title compound.

¹H NMR (500 MHz, CDCl₃): δ 7.82 (d, J=1.8 Hz, 1H), 7.53-7.48 (m, 2H), 4.92 (s, 2H), 2.02 (s, 1H).

{5-Bromo-2-[(difluoromethyl)sulfanyl]phenyl}methanol

(5-Bromo-2-sulfanylphenyl)methanol (0.50 g, 2.8 mmol) was dissolved in acetonitrile (11.4 mL) followed by the addition of water (11.4 mL) and solid potassium hydroxide (2.56 g, 45.6 mmol). The mixture was plunged into a −78° C. bath and when the mixture began to freeze diethyl [bromo(difluoro)methyl]phosphonate (1.22 g, 4.56 mmol) was added all at once and the cold bath was removed. The mixture was allowed to warm to ambient temperature and was stirred for 20 minutes. The mixture was then partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous MgSO₄ and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-25% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.

¹H NMR (500 MHz, CDCl₃):

7.76 (s, 1H), 7.47 (m, 2H), 6.80 (t, J=56.5 Hz, 1H), 4.87 (s, 2H), 1.96 (br s, 1H).

1-Bromo-4-[(fluoromethyl)sulfanyl]benzene

1-Bromo-4-(methylsulfinyl)benzene (1.50 g, 6.85 mmol) was dissolved in 1,2-DCE (13.7 mL) and stirred at ambient temperature. BAST (3.79 g, 17.1 mmol) was added dropwise followed by zinc iodide (0.07 g, 0.21 mmol). The reaction vessel was sealed and the mixture was heated to 40° C., allowed to stir for 24 hours, and then allowed to cool to ambient temperature. The mixture was partitioned between EtOAc and water, the layers were separated and the organic layer was dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.

¹H NMR (500 MHz, CDCl₃): δ 7.49-7.44 (m, 2H), 7.38-7.33 (m, 2H), 5.69 (d, J=52.8 Hz, 2H).

{5-Bromo-2-[(trifluoromethyl)sulfonyl]phenyl}methanol

A mixture of m-CPBA (452 mg, 2.62 mmol) and {5-bromo-2-[(trifluoromethyl)thio]phenyl}methanol (188 mg, 0.655 mmol) in DCM (6.6 mL) was heated to 40° C. and stirred in a microwave reaction vial for 30 hours. After cooling to 23° C., the reaction mixture was partitioned between EtOAc and aqueous potassium bisulfate solution (40% w/w). The organic layer was washed sequentially with saturated aqueous NaHCO₃, brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-30%, EtOAc/hexanes) to afford the title compound.

¹H NMR (500 MHz, CDCl₃): δ 8.06 (d, J=1.7 Hz, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.73 (dd, J=8.6, 2.0 Hz, 1H), 5.01 (s, 2H), 2.56 (s, 1H).

TABLE 3 discloses intermediates 12-2 and 12-3 that were prepared according to Schemes #6-8 following similar procedures described for Intermediate #12-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 3 Intermediate Structure Compound Name ¹H NMR δ (ppm) 12-2

{5-bromo-2- [(difluoromethyl)sulfonyl]- phenyl}methanol ¹H NMR (500 MHz, CDCl₃): δ 7.93 (d, J = 1.9 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.72 (dd, J = 8.3, 1.9 Hz, 1H), 6.33 (t, J = 53.6 Hz, 1H), 4.98 (d, J = 6.4 Hz, 2H), 2.53 (t, J = 6.4 Hz, 1H). 12-3

1-bromo-4- [(fluoromethyl)sulfonyl]- benzene ¹H NMR (500 MHz, CDCl₃): δ 7.86-7.80 (m, 2H), 7.80-7.74 (m, 2H), 5.13 (d, J = 46.9 Hz, 2H).

5-Bromo-2,3-dihydro-1-benzothiophene-3-ol 1,1-dioxide

Step A. 5-Bromo-1-benzothiophene 1,1-dioxide

5-Bromo-1-benzothiophene (1.50 g, 7.04 mmol) was dissolved in chloroform (47 mL) and allowed to stir vigorously at ambient temperature. m-CPBA (4.34 g, 17.6 mmol) was added in three portions and the resulting mixture was maintained at ambient temperature for 16 hours. The mixture was then diluted with 1M aqueous sodium thiosulfate and extracted with EtOAc. The organic layer was again washed with 1M aqueous sodium thiosulfate, saturated aqueous NaHCO₃, brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-30% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.

¹H NMR (600 MHz, CDCl₃): δ 7.65 (dd, J=7.9, 1.8 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.50 (d, J=1.8 Hz, 1H), 7.15 (d, J=6.9 Hz, 1H), 6.74 (d, J=6.9 Hz, 1H).

Step B. 5-Bromo-2,3-dihydro-1-benzothiophene-3-ol 1,1-dioxide

5-Bromo-1-benzothiophene 1,1-dioxide (100 mg, 0.41 mmol) was suspended in 1N aqueous sodium hydroxide (2.0 mL), heated to 100° C. in a microwave, and allowed to stir for 15 minutes. The mixture was then allowed to cool to ambient temperature before the mixture was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was used without further purification. LRMS (ESI) calc'd for C₈H₇BrO₃S [M+Na]⁺: 285. Found: 285.

5-Bromo-2,3,3-trimethyl-2,3-dihydro-1H-isoindol-1-one

5-Bromo-2,3-dihydro-1H-isoindol-1-one (150 mg, 0.71 mmol) was dissolved in DMF (3.5 mL) and stirred at ambient temperature. NaH (85 mg, 2.12 mmol, 60% dispersion in oil) was carefully added in two portions, and the resulting mixture was allowed to stir for 15 minutes before MeI (151 mg, 1.06 mmol) was added. The mixture was allowed to stir at ambient temperature for 30 minutes before water (10 mL) was carefully added. The mixture was extracted with EtOAc, and the organic layer was washed with water, brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.

LRMS (ESI) calc'd for C₁₁H₁₂BrNO [M+H]⁺: 254. Found: 254.

5-Bromo-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-isoindol-1-one

5-Bromo-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.47 mmol) was dissolved in DMF (4.7 mL) and stirred at 0° C. NaH (38 mg, 0.94 mmol, 60% dispersion in oil) was carefully added in two portions, and the resulting mixture was allowed to stir at 0° C. for 15 minutes before 2,2,2-trifluoroethyl trifluoromethanesulfonate (110 mg, 0.47 mmol) was added. The mixture was allowed to stir at 0° C. for 30 minutes before saturated aqueous NaHCO₃ (10 mL) was carefully added, and the mixture was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.

LRMS (ESI) calc'd for C₁₀H₇BrF₃NO [M+H]⁺: 294. Found: 294.

tert-Butyl (5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)acetate

5-Bromo-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.47 mmol) was dissolved in DMF (4.7 mL) and stirred at 0° C. NaH (38 mg, 0.94 mmol, 60% dispersion in oil) was carefully added in two portions, and the resulting mixture was allowed to stir at 0° C. for 15 minutes before tert-butyl bromoacetate (92 mg, 0.47 mmol) was added. The mixture was allowed to stir at 0° C. for 30 minutes before saturated aqueous NaHCO₃ (10 mL) was carefully added. The mixture was extracted with EtOAc, and the organic layer was washed with water, brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. LRMS (ESI) calc'd for C₁₄H₁₆BrNO₃ [M+Na]⁺: 348. Found: 348.

1-[(3-Bromobenzyl)oxy]-2-methylpropan-2-ol

Step A. Methyl [(3-bromobenzyboxy]acetate

Methyl hydroxyacetate (0.80 g, 8.8 mmol) was dissolved in THF (10 mL) and allowed to stir at 0° C. under a nitrogen atmosphere. NaH (0.40 g, 9.6 mmol, 60% dispersion in oil) was added portionwise over approximately 5 minutes. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. 1-Bromo-3-(bromomethyl)benzene (2.0 g, 8.0 mmol) was added in a single portion and the resulting mixture was heated to 40° C. After 4 hours, the reaction mixture was allowed to cool to ambient temperature and partitioned between water and EtOAc. The layers were separated, and the organic layer was washed with saturated aqueous NaHCO₃, brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound, which was carried forward without further purification.

¹H NMR (600 MHz, CDCl₃): δ 7.53-7.50 (m, 1H), 7.42-7.38 (m, 1H), 7.30-7.17 (m, 2H), 4.57 (s, 2H), 4.09 (s, 2H), 3.74 (s, 3H).

Step B. 1-[(3-Bromobenzyl)oxy]-2-methylpropan-2-ol

Methyl [(3-bromobenzyl)oxy]acetate (2.0 g, 7.7 mmol) was dissolved in THF (10 mL) and was allowed to stir under a nitrogen atmosphere. Methylmagnesium bromide (7.7 mL, 23 mmol, 3.0 M in THF) was added dropwise. The reaction mixture was allowed to stir at ambient temperature for 4 hours before the reaction was quenched with water and the mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO₃, brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 2-70% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to the title compound.

¹H NMR (600 MHz, CDCl₃): δ 7.46 (s, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.25-7.18 (m, 2H), 4.52 (s, 2H), 3.29 (s, 2H), 1.21 (s, 6H).

Step A-B. 2-[1-(3-Bromobenzyl)-1H-1,2,3-triazol-4-yl]propan-2-ol

To a solution of 1-bromo-3-(bromomethyl)benzene (5.0 g, 20 mmol) in DMSO (40 mL) was added sodium azide (1.3 g, 20 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 hours before it was diluted with water and extracted with diethyl ether (2×). The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was dissolved in ^(t)BuOH (65 mL and water (39 mL) and to this mixture was added 2-methylbut-3-yn-2-ol (2.3 g, 27 mmol), and then a solution of copper (II) sulfate pentahydrate (0.26 g, 1.0 mmol) in water (10 mL) followed by a solution of sodium ascorbate (0.83 g, 4.2 mmol) in water (8 mL). The resulting mixture was allowed to stir at ambient temperature for 2 hours before it was diluted with water and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was used without further purification.

LRMS (ESI) calc'd for C₁₂H₁₄BrN₃O [M+H]⁺: 296. Found: 296.

tert-Butyl 4-(cyanomethylidene)piperidine-1-carboxylate

To a three necked round bottom flask equipped with a mechanical stirring bar was added potassium tert-butoxide (263 mL, 263 mmol, 1.0 M in THF) and THF (200 mL). The mixture was cooled to 0° C., followed by the addition of diethyl (cyanomethyl)phosphonate (43.7 mL, 276 mmol) slowly by syringe. The reaction mixture was maintained at 0° C. for 10 minutes, then warmed to ambient temperature and maintained for 1 hour. The mixture was cooled to 0° C. and treated with the dropwise addition of tert-butyl 4-oxopiperidine-1-carboxylate (50.0 g, 251 mmol) in THF (150 mL) over 30 minutes. After addition, the mixture was maintained at 0° C. for 20 minutes, then warmed to ambient temperature and maintained for 18 hours. The reaction mixture was then diluted with water (800 mL) and extracted with EtOAc (700 mL×2). The combined organic extracts were washed with water, brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound as a light pink solid.

¹H-NMR (600 MHz, CDCl₃) δ 5.19 (S, 1H), 3.48-3.53 (m, 4H), 2.56 (t, J=5.4 Hz, 2H), 2.33 (t, J=5.4 Hz, 2H), 1.47 (s, 9H).

TABLE 4 discloses Intermediates 19-2 through 19-24 that were prepared according to Scheme #12 and 13 following similar procedures described for Intermediate #19-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 4 Exact Mass [M + H]⁺ or Intermediate Structure Compound Name ¹H NMR δ (ppm) 19-2 

(2E and Z)-4-methylpent- 2-enenitrile ¹H NMR (600 MHz, CDCl₃): 1:1 E:Z δ 6.68 (dd, J = 16.4, 6.6, 1H), 5.27-5.23 (m, 1H), 1.96-1.82 (m, 1H), 1.04 (d, J = 6.8, 6H); ¹H NMR (600 MHz, CDCl₃): δ 6.31-6.24 (m, 1H), 5.18 (d, J = 10.9, 1H), 1.77-1.64 (m, 1H), 1.06 (d, J = 6.6, 6H). 19-3 

(2E and Z)-4,4- dimethylpent-2-enenitrile ¹H NMR (600 MHz, CDCl₃): 1:1 E:Z δ 6.70 (d, J = 16.6, 1H), 5.20 (d, J = 12.3, 5.20, 1H), 1.22 (s, 9H); ¹H NMR (600 MHz, CDCl₃): δ 6.32 (d, J = 12.3, 1H), 5.22 (d, J = 16.6, 1H), 1.05 (s, 9H). 19-4 

(2E and Z)-5,5- dimethylhex-2-enenitrile ¹H NMR (600 MHz, CDCl₃): 1:1 E:Z δ 6.72 (dt, J = 15.9, 7.9, 1H), 5.30 (dt, J = 15.2, 1.49, 1H), 2.08 (dd, J = 7.9, 1.3, 2H), 0.91 (s, 9H). ¹H NMR (600 MHz, CDCl₃) δ 6.53 (dt, J = 11.0, 8.0, 1H), 5.37 (dt, J = 11.0, 1.1, 1H), 2.30 (d, J = 8.0, 2H), 2, 0.95 (s, 9H). 19-5 

(2E and 2Z)-3- cyclopropylprop-2- enenitrile ¹H NMR (600 MHz, CDCl₃): 5:3 E:Z δ 6.10-6.04 (m, 1H), 5.30 (d, J = 16.1 Hz, 1H), 1.58-1.50 (m, 1H), 1.04-0.92 (m, 4H); ¹H NMR (600 MHz, CDCl₃): δ 5.74 (t, J = 10.6, 1H), 5.12 (d, J = 10.6 Hz, 1H), 1.98-1.90 (m, 1H), 0.65- 0.58 (m, 4H). 19-6 

(2E and Z)-3- cyclopropylbut-2- enenitrile ¹H NMR (600 MHz, CDCl₃): 3:1 E:Z δ 5.09-5.07 (m, 1H), 1.82-1.81 (m, 3H), 1.53 (t, J = 1.1, 1H), 0.87-0.81 (m, 2H), 0.70-0.65 (m, 2H); ¹H NMR (600 MHz, CDCl₃): δ 5.07-5.06 (m, 1H), 2.17- 2.11 (m, 1H), 1.59-1.54 (m, 3H), 0.94-0.88 (m, 2H), 0.78-0.74 (m, 2H). 19-7 

(2E and Z)-3- cyclobutylprop-2- enenitrile ¹H NMR (600 MHz, CDCl₃): 1:1 E:Z δ 6.78 (dd, J = 16.3, 6.8, 1H), 5.21 (dd, J = 16.3, 1.5, 1H), 2.30-1.85 (m, 7H); ¹H NMR (600 MHz, CDCl₃): δ 6.53 (dd, J = 10.8, 9.4, 1H), 5.12 (dd, J = 10.9, 0.8, 1H), 2.30-1.85 (m, 7H). 19-8 

(2E and 2Z)-3- cyclopentylprop-2- enenitrile ¹H NMR (600 MHz, CDCl₃): 4:5 E:Z δ 6.68-6.64 (m, 1H), 5.26 (d, J = 17.6 Hz, 1H), 2.60-2.50 (m, 1H), 1.96-1.28 (m, 8H); ¹H NMR (600 MHz, CDCl₃): δ 6.34 (t, J = 10.6, 1H), 5.18 (d, J = 10.9 Hz, 1H), 3.04-2.94 (m, 1H), 1.96- 1.28 (m, 8H). 19-9 

(2E and 2Z)-3- (tetrahydrofuran-3-yl)prop- 2-enenitrile ¹H NMR (600 MHz, CDCl₃): 1:1 E:Z δ 6.63 (dd, J = 16.3, 8.8, 1H), 6.39 (t, J = 10.5, 1H), 5.40-5.35 (m, 1H), 5.31 (d, J = 10.8, 1H), 3.97- 3.87 (m, 4H), 3.82-3.77 (m, 2H), 3.56-3.50 (m, 2H), 3.46-3.39 (m, 1H), 3.02- 2.92 (m, 1H), 2.27-2.27 (m, 1H), 2.19-2.13 (m, 1H), 1.79- 1.67 (m, 2H). 19-10

(2E and 2Z)-3-(tetrahydro- 2H-pyran-4-yl)prop-2- enenitrile ¹H NMR (600 MHz, CDCl₃): 1:1 E:Z δ 6.64 (dd, J = 16.5, 6.6, 1H), 5.29 (dd, J = 16.5, 1.6, 1H), 1.77-1.66 (m, 1H), 1.65-1.59 (m, 4H), 1.56- 1.43 (m, 4H); ¹H NMR (600 MHz, CDCl₃): 6.28 (dd, J = 10.8, 9.8, 1H), 5.27-5.25 (m, 1H), 3.99-3.93 (m, 4H), 3.42 (dtd, J = 34.3, 11.8, 2.2, 4H), 2.43-2.33 (m, 1H). 19-11

(2E and 2Z)-3-(tetrahydro- 2H-pyran-3-yl)prop-2- enenitrile ¹H NMR (600 MHz, CDCl₃): 3:5 E:Z δ 6.58 (dd, J = 16.5, 7.3, 1H), 5.36 (dd, J = 16.5, 1.4, 1H), 3.88-1.44 (m, 9H); ¹H NMR (600 MHz, CDCl₃): δ 6.37 (t, J = 10.5 1H), 5.33 (dd, J = 11.0, 0.6, 1H), 3.88- 1.44 (m, 9H). 19-12

(2E and 2Z)-4-(tetrahydro- 2H-pyran-4-yl)but-2- enenitrile ¹H NMR (600 MHz, CDCl₃): 1:1 E:Z δ 6.66 (dt, J = 16.2, 7.6, 1H), 5.33 (dt, J = 16.3, 1.5, 1H), 3.97-3.89 (m, 8H), 2.18-2.14 (m, 2H), 1.78- 1.54 (m, 1H); ¹H NMR (600 MHz, CDCl₃): 6.48 (dt, J = 10.9, 7.8, 1H), 5.37 (dt, J = 10.9, 1.2, 1H), 3.38-3.31 (m, 8H), 2.37 (t, J = 7.3, 2H), 1.78-1.54 (m, 1H). 19-13

tert-butyl 4-[(E and Z)-2- cyanoethenyl]piperidine-1- carboxylate ¹H NMR (500 MHz, CDCl₃): 18:5 E:Z δ 6.70-6.62 (m, 1H), 5.36-5.28 (m, 1H), 4.25-4.05 (m, 2H), 2.85-2.65 (m, 2H), 2.35-2.25 (m, 1H), 1.75-1.68 (m, 2H), 1.46 (s, 9H), 1.38- 1.20 (m, 2H); ¹H NMR (500 MHz, CDCl₃): δ 6.28 (t, J = 10.4, 1H), 5.29 (d, J = 10.9 Hz, 1H), 4.25-4.00 (m, 2H), 2.90-2.70 (m, 3H), 1.75-1.65 (m, 2H), 1.46 (s, 9H), 1.43- 1.30 (m, 2H). 19-14

tert-butyl 3- (cyanomethylidene) azetidine-1-carboxylate ¹H NMR (600 MHz, CDCl₃): δ 5.38-5.35 (m, 1H), 4.69 (m, 2H), 4.61-4.58 (m, 2H), 1.44 (s, 9H). 19-15

tert-butyl 3-[(E and Z)-2- cyanoethenyl]pyrrolidine 1-carboxylate ¹H NMR (600 MHz, CDCl₃): 4:1 E:Z δ 6.37 (t, J = 10.6 Hz, 1H), 5.35 (d, J = 10.6 Hz, 1H), 3.70-2.86 (m, 5H), 2.20- 2.00 (m, 1H), 1.84-1.70 (m, 1H), 1.43 (s, 9H); ¹H NMR (600 MHz, CDCl₃): δ 6.68- 6.60 (m, 1H), 5.35 (dd, J = 16.4, 1.2 Hz, 1H), 3.70-2.86 (m, 5H), 2.20-2.00 (m, 1H), 1.84-1.70 (m, 1H), 1.43 (s, 9H). 19-16

tert-butyl 4-[(1E and Z)-1- cyanoprop-1-en-2- yl]piperidine-1- carboxylate Calc'd 251, Found 195 (M + H—C₄H₈) 19-17

tert-butyl 4-[(E and Z)-2- cyanoethenyl]-4- fluoropiperidine-1- carboxylate Calc'd 255, Found 199 (M + H—C₄H₈) 19-18

tert-butyl 4- (cyanomethylidene) cyclohexanecarboxylate ¹H NMR (600 MHz, CDCl₃): 5.07 (s, 1H), 2.82 (dt, J = 14.4 and 4.8 Hz, 1H), 2.38- 2.46 (m, 2H), 2.16-2.26 (m, 2H), 1.95-2.06 (m, 2H), 1.61- 1.71 (m, 2H). 19-19

tert-butyl [4- (cyanomethylidene) cyclohexyl]carbamate used as crude 19-20

oxetan-3- ylideneacetonitrile ¹H NMR (600 MHz, CDCl₃): 5.33-5.35 (m, 2H), 5.24-5.26 (m, 2H), 5.21-5.22 (m, 1H). 19-21

tetrahydro-4H-pyran-4- ylideneacetonitrile used as crude 19-22

3-(cyanomethylidene) cyclobutanecarbonitrile ¹H NMR (600 MHz, CDCl₃): 5.27-5.29 (m, 1H), 3.32-3.43 (m, 2H), 3.25-3.41 (m, 3H). 19-23

1,4-dioxaspiro[4.5]dec-8- ylideneacetonitrile used as crude 19-24

tert-butyl 6- (cyanomethylidene)-2- azaspiro[3.3]heptane-2- carboxylate ¹H NMR (600 MHz, CDCl₃): 5.18 (s, 1H), 3.93-3.98 (m, 4H), 3.11 (s, 2H), 3.01 (s, 2H).

tert-Butyl (4E and 4Z)-4-(cyanomethylidene)-3-fluoropiperidine-1-carboxylate

To a solution of NaH (0.27 g, 6.6 mmol, 60% in mineral oil) in DMF (10 mL) was added diethyl (cyanomethyl)phosphonate (1.5 g, 6.6 mmol). The mixture was stirred at ambient temperature for 30 minutes before tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (0.70 g, 3.3 mmol) was added. The resulting mixture was stirred for 1 hour before the reaction was quenched with water and the mixture was concentrated in vacuo. The crude residue was purified by MPLC on silica gel to afford the title compound. LRMS (ESI) calc'd for (C₁₂H₁₈FN₂O₂) [M+H]⁺: 241. Found 241.

tert-Butyl 4-(1-cyanoethylidene)piperidine-1-carboxylate

To a solution of MeI (1.4 g, 10 mmol) in DMF was added NaH (0.40 g, 10 mmol, 60% in mineral oil), followed by diethyl (cyanomethyl)phosphonate (2.3 g, 10 mmol). The mixture was stirred at ambient temperature. After 30 minutes another batch of NaH (0.40 g, 10 mmol, 60% in mineral oil) was added, followed by tert-butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10 mmol). The resulting mixture was stirred for 30 minutes before the reaction was quenched with water and the mixture was concentrated in vacuo. The crude residue was purified by MPLC on silica gel to afford the title compound. LRMS (ESI) calc'd for C₁₃H₂₁N₂O₂ [M+H]⁺237. Found 237.

tert-Butyl 4-[cyano(cyclopropyl)methylidene]piperidine-1-carboxylate

tert-Butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10 mmol) and cyclopropylacetonitrile (0.97 g, 12 mmol) were dissolved in THF (20 mL), heated to reflux, and allowed to stir for 3 hours. The mixture was then cooled to ambient temperature and concentrated in vacuo. The residue was purified by MPLC on silica gel to afford the title compound as a white solid.

LRMS (ESI) calc'd for C₁₅H₂₃N₂O₂ [M+H]⁺263. Found 263.

Step A-B. [1-(Ethylsulfonyl)azetidin-3-ylidene]acetonitrile

tert-Butyl 3-(cyanomethylidene)azetidine-1-carboxylate (5.0 g, 26 mmol) was dissolved in 4M HCl in dioxane (25.7 mL) and allowed to stir at ambient temperature for 16 hours. The mixture was concentrated to dryness in vacuo, then dissolved in DCM (30.0 mL) and cooled to −10° C. DIPEA (11.6 g, 90.0 mmol) was added followed by ethanesulfonyl chloride (5.0 g, 39 mmol). The resulting mixture was allowed to stir for 7 hours before the mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 5-70% EtOAc/heptane). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.

LRMS (ESI) calc'd for C₇H₁₀N₂O₂S [M+H]⁺: 187. Found: 187.

2,2,2-Trifluoroethyl 4-(cyanomethylene)piperidine-1-carboxylate

Step A. 4-(Cyanomethylidene)piperidinium trifluoroacetate

tert-Butyl 4-(cyanomethylene)piperidine-1-carboxylate (5.0 g, 22 mmol) was dissolved in DCM (75.0 mL). TFA (8.7 mL, 112 mmol) was added, and the resulting mixture was allowed to stir at ambient temperature for 2 hours. The mixture was concentrated in vacuo to afford the title compound.

LRMS (ESI) calc'd for C₇H₁₀N₂ [M+H]⁺: 123. Found: 123.

Step B. 2,2,2-Trifluoroethyl 4-(cyanomethylene)piperidine-1-carboxylate

2,2,2-Trifluoroethanol (1.6 mL, 22 mmol) and TEA (6.2 mL, 45 mmol) were dissolved in acetonitrile (200 mL). N,N-disuccinimidyl carbonate (8.6 g, 34 mmol) was added and the resulting mixture was stirred at ambient temperature for 90 minutes. 4-(Cyanomethylidene)piperidinium trifluoroacetate (5.3 g, 23 mmol) in DMSO (10 mL) was then added, followed by TEA (6.2 mL, 45 mmol). The resulting mixture was stirred at 50° C. for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc and washed sequentially with saturated NaHCO₃ (aq) and water. The organic layer was dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-5% MeOH in DCM) to afford the title compound. LRMS (ESI) calc'd for C₁₀H₁₁F₃N₂O₂ [M+H]⁺: 249. Found: 249.

[1-(3,4-Dimethoxyphenyl)piperidin-4-ylidene]acetonitrile

Step A. 4-(Cyanomethylidene)piperidinium chloride

tert-Butyl 4-(cyanomethylidene)piperidine-1-carboxylate (20 g, 90 mmol) was dissolved in 4M HCl in dioxane and allowed to stir at ambient temperature for 2 hours. The mixture was then concentrated in vacuo to afford the title compound.

LRMS (ESI) calc'd for C₇H₁₀N₂ [M+H]⁺: 123. Found: 123.

Step B. [1-(3,4-Dimethoxyphenyl)piperidin-4-ylidene]acetonitrile

In a sealed tube, 4-(cyanomethylidene)piperidinium chloride (16 mg, 0.10 mmol), Pd₂(dba)₃ (14 mg, 0.015 mmol), X-Phos (20 mg, 0.020 mmol), 4-bromo-1,2-dimethoxybenzene (33 mg, 0.15 mmol), and Cs₂CO₃ (98 mg, 0.30 mmol) were suspended in t-BuOH (0.5 mL). The reaction mixture was purged with argon for 5 minutes, the reaction flask was capped, and heated to 90° C. for 12 hours. The reaction was then cooled to ambient temperature and diluted with DMF:MeCN (1.0 mL, 50:50). To this mixture, Silica Supported-DMT (0.50 mmol, 0.57 mmol/g) followed by Silica Supported-Isocyanate (0.15 mmol, 1.33 mmol/g) was added. The resulting mixture was then shaken at 50° C. for 4 hours. The mixture was then passed through a nylon syringe filter (0.45 μm), and the filtrate was concentrated in vacuo to afford the title compound. The crude residue was used without further purification.

LRMS (ESI) calc'd for C₁₅H₁₈N₂O₂ [M+H]⁺: 259. Found: 259.

TABLE 5 depicts intermediates 25-2 through 25-55 that were prepared according to Scheme #14 following similar procedures described for Intermediates #25-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 5 Exact Mass Intermediate Structure Compound Name [M+ H]⁺ 25-2 

[1-(isoquinolin-5-yl)piperidin-4- ylidene]acetonitrile Calc'd 250, Found 250 25-3 

[1-(isoquinolin-8-yl)piperidin-4- ylidene]acetonitrile Calc'd 250, Found 250 25-4 

2-(1-(2-methylpyridin-4- yl)piperidin-4- ylidene)acetonitrile Calc'd 214, Found 214 25-5 

2-(1-(5-methylpyridin-3- yl)piperidin-4- ylidene)acetonitrile Calc'd 214, Found 214 25-6 

2-(1-(2-methoxypyridin-4- yl)piperidin-4- ylidene)acetonitrile Calc'd 230, Found 230 25-7 

2-(1-(6-(2-hydroxypropan-2- yl)pyridin-2-yl)piperidin-4- ylidene)acetonitrile Calc'd 258, Found 258 25-8 

2-(1-(5-(trifluoromethyl)pyridin- 3-yl)piperidin-4- ylidene)acetonitrile Calc'd 268, Found 268 25-9 

2-(1-(4-(2,2,2-trifluoro-1- hydroxyethyl)phenyl)piperidin- 4-ylidene)acetonitrile Calc'd 297, Found 297 25-10

2-(1-(6-(2- hydroxyethoxy)pyridin-2- yl)piperidin-4- ylidene)acetonitrile Calc'd 260, Found 260 25-11

2-(1-(4-fluoro-3- methoxyphenyl)piperidin-4- ylidene)acetonitrile Calc'd 247, Found 247 25-12

2-(1-(6- (difluoromethoxy)pyridin-3- yl)piperidin-4- ylidene)acetonitrile Calc'd 266, Found 266 25-13

2-(1-(5,6-dimethylpyridin-3- yl)piperidin-4- ylidene)acetonitrile Calc'd 228, Found 228 25-14

2-(1-(6-isopropoxypyridin-2- yl)piperidin-4- ylidene)acetonitrile Calc'd 258, Found 258 25-15

2-(1-(6-ethoxypyridin-2- yl)piperidin-4- ylidene)acetonitrile Calc'd 244, Found 244 25-16

2-(1-(3- cyclopropylphenyl)piperidin-4- ylidene)acetonitrile Calc'd 239, Found 239 25-17

6-(4-(cyanomethylene)piperidin- 1-yl)picolinonitrile Calc'd 225, Found 225 25-18

2-(1-(5- (difluoromethoxy)pyridin-2- yl)piperidin-4- ylidene)acetonitrile Calc'd 266, Found 266 25-19

2-(1-(6-methylpyridin-2- yl)piperidin-4- ylidene)acetonitrile Calc'd 214, Found 214 25-20

5-(4-(cyanomethylene)piperidin- 1-yl)nicotinonitrile Calc'd 225, Found 225 25-21

2-(1-(6-fluoropyridin-3- yl)piperidin-4- ylidene)acetonitrile Calc'd 218, Found 218 25-22

2-(1-(3-methoxypyridin-2- yl)piperidin-4- ylidene)acetonitrile Calc'd 230, Found 230 25-23

2-(1-(pyrimidin-5-yl)piperidin- 4-ylidene)acetonitrile Calc'd 201, Found 201 25-24

2-(1-(2-methoxypyrimidin-5- yl)piperidin-4- ylidene)acetonitrile Calc'd 231, Found 231 25-25

4-(4-(cyanomethylene)piperidin- 1-yl)benzonitrile Calc'd 224, Found 224 25-26

2-(1-(3-fluorophenyl)piperidin- 4-ylidene)acetonitrile Calc'd 217, Found 217 25-27

2-(1-(6-(trifluoromethyl)pyridin- 3-yl)piperidin-4- ylidene)acetonitrile Calc'd 268, Found 268 25-28

2-(1-(2-methylpyridin-3- yl)piperidin-4- ylidene)acetonitrile Calc'd 214, Found 214 25-29

2-(1-(pyridin-3-yl)piperidin-4- ylidene)acetonitrile Calc'd 200, Found 200 25-30

2-(1-(4-methylpyridin-2- yl)piperidin-4- ylidene)acetonitrile Calc'd 214, Found 214 25-31

2-(1-(5-fluoro-2- methylphenyl)piperidin-4- ylidene)acetonitrile Calc'd 231, Found 231 25-32

2-(1-(4-methylpyridin-3- yl)piperidin-4- ylidene)acetonitrile Calc'd 214, Found 214 25-33

2-(1-(3-fluoro-4- methylphenyl)piperidin-4- ylidene)acetonitrile Calc'd 231, Found 231 25-34

methyl 6-(4- (cyanomethylene)piperidin-1- yl)picolinate Calc'd 258, Found 258 25-35

2-(1-(6-ethoxypyridin-3- yl)piperidin-4- ylidene)acetonitrile Calc'd 244, Found 244 25-36

2-(1-(5-methoxypyridin-3- yl)piperidin-4- ylidene)acetonitrile Calc'd 230, Found 230 25-37

2-(1-(4-fluorophenyl)piperidin- 4-ylidene)acetonitrile Calc'd 217, Found 217 25-38

2-(1-(p-tolyl)piperidin-4- ylidene)acetonitrile Calc'd 213, Found 213 25-39

2-(1-(3,5- difluorophenyl)piperidin-4- ylidene)acetonitrile Calc'd 235, Found 235 25-40

2-(1-(2- methoxyphenyl)piperidin-4- ylidene)acetonitrile Calc'd 229, Found 229 25-41

2-(1-(4-fluoro-3- methylphenyl)piperidin-4- ylidene)acetonitrile Calc'd 231, Found 231 25-42

2-(1-(2-fluoro-3- methylphenyl)piperidin-4- ylidene)acetonitrile Calc'd 231, Found 231 25-43

2-(1-(4-fluoropyridin-2- yl)piperidin-4- ylidene)acetonitrile Calc'd 218, Found 218 25-44

2-(1-(3,4- difluorophenyl)piperidin-4- ylidene)acetonitrile Calc'd 235, Found 235 25-45

2-(1-(pyridin-4-yl)piperidin-4- ylidene)acetonitrile Calc'd 200, Found 200 25-46

2-(1-(4-methylpyrimidin-5- yl)piperidin-4- ylidene)acetonitrile Calc'd 215, Found 215 25-47

2-(1-(5-methylpyridin-3- yl)piperidin-4- ylidene)acetonitrile Calc'd 214, Found 214 25-48

2-(1-(6-(2-hydroxy-2- methylpropyl)pyridin-2- yl)piperidin-4- ylidene)acetonitrile Calc'd 272, Found 272 25-49

2-(1-(6-(fluoromethyl)pyridin-2- yl)piperidin-4- ylidene)acetonitrile Calc'd 232, Found 232 25-50

2-(1-(2-fluoropyridin-3- yl)piperidin-4- ylidene)acetonitrile Calc'd 218, Found 218 25-51

2-(1-(6-methylpyridin-3- ylpiperidin-4- ylidene)acetonitrile Calc'd 214, Found 214 25-52

2-(1-(6-methoxypyridin-3- yl)piperidin-4- ylidene)acetonitrile Calc'd 230, Found 230 25-53

2-(1-(6-fluoropyridin-2- yl)piperidin-4- ylidene)acetonitrile Calc'd 218, Found 218 25-54

2-(1-(4-(trifluoromethyl)pyridin- 2-yl)piperidin-4- ylidene)acetonitrile Calc'd 268, Found 268 25-55

2-(1-(6-fluoro-5-methylpyridin- 3-yl)piperidin-4- ylidene)acetonitrile Calc'd 232, Found 232

Step A-C. tert-Butyl 3-cyanocyclohex-3-ene-1-carboxylate

tert-Butyl 3-oxocyclohexanecarboxylate (1.35 g, 6.81 mmol) was taken up in water (11.4 mL) and stirred at ambient temperature. Sodium metabisulfite (0.75 g, 3.9 mmol) was added and the mixture was allowed to stir for 40 minutes. Diethyl ether (11.4 mL) was added, followed by potassium cyanide (0.70 g, 11 mmol). The resulting mixture was allowed to stir vigorously for 1 hour before it was partitioned between diethyl ether and water. The organic layer was washed with water, brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue, used without further purification, was dissolved in DCM (22.0 mL). DIPEA (1.07 g, 8.26 mmol) was added and the resulting mixture was cooled to 0° C. Methanesulfonyl chloride (0.69 g, 6.1 mmol) was added dropwise and the resulting mixture was maintained at 0° C. for 20 minutes then allowed to warm to ambient temperature. The mixture was partitioned between DCM and water. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue, used without further purification, was dissolved in pyridine (13.6 mL) and heated to 95° C. for 20 hours. The mixture was then allowed to cool to ambient temperature and was concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-45% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.

¹H NMR (500 MHz, CDCl₃): δ 6.63-6.58 (m, 1H), 2.54-2.48 (m, 1H), 2.44-2.40 (m, 2H), 2.36-2.16 (m, 2H), 2.02-1.94 (m, 1H), 1.71-1.63 (m, 1H), 1.44 (s, 9H).

TABLE 6 depicts intermediates 26-2 through 26-4 that were prepared according to Scheme #15 following similar procedures described for Intermediate #26-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 6 Intermediate Structure Compound Name ¹H NMR δ (ppm) 26-2

methyl 3-cyanocyclohex- 3-ene-1-carboxylate ¹H NMR (500 MHz, CDCl₃): δ 6.66-6.60 (m, 1H), 3.70 (s, 3H), 2.68-2.60 (m, 1H), 2.52- 2.44 (m, 2H), 2.40-2.18 (m, 2H), 2.10-2.00 (m, 1H), 1.80- 1.66 (m, 1H). 26-3

4-tert-butyl (4- cyanocyclohex-3-en-1- yl)carbamate ¹H NMR (600 MHz, CDCl₃): δ 6.53-6.50 (m, 1H), 4.46 (s, 1H), 3.77 (s, 1H), 2.58 (br d, J = 19.9 Hz, 1H), 2.48-2.27 (br d, J = 19.2 Hz, 2H), 2.03 (ddq, J = 19.3, 8.0, 3.6, 1H), 1.96-1.91 (m, 1H), 1.63-1.56 (m, 1H), 1.42 (s, 9H). 26-4

tert-butyl 4-cyano-3,6- dihydropyridine-1(2H)- carboxylate ¹H NMR (500 MHz, CDCl₃): δ 6.55 (br s, 1H), 4.05 (m, 2H), 3.55 (t, J = 5.6 Hz, 2H), 2.34 (br s, 2H), 1.46 (s, 9H).

Step A-B. 4-Methylcyclohex-1-ene-1-carbonitrile

4-Methylcyclohexanone (1.0 g, 8.9 mmol) was added to a stirred solution of water (8.9 mL) containing sodium metabisulfite (0.98 g, 5.2 mmol). The resulting mixture was allowed to stir at ambient temperature for 15-30 minutes before diethyl ether (8.9 mL) was added followed by potassium cyanide (0.91 g, 14 mmol). The biphasic mixture was stirred vigorously for at least 30 minutes before the layers were partitioned and the organic layer was washed with water, followed by brine. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo (23° C. water bath) to afford 4-methyl-1-hydroxycyclohexanecarbonitrile as a crude residue, which was carried forward without further purification. The crude residue (0.50 g, 3.6 mmol) was combined with pyridine (18.3 mL, 226 mmol), and POCl₃ (1.34 mL, 14.4 mmol) in a microwave vial and sealed. The reaction mixture was heated to reflux for 16 hours. The reaction mixture was then cooled to ambient temperature, diluted with diethyl ether, and washed with 2N aqueous HCl saturated with sodium chloride (3×). The organic layer was washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo (23° C. water bath) to afford the title compound as an oil.

¹H NMR (600 MHz, CDCl₃): δ 6.59-6.56 (m, 1H), 2.28-2.20 (m, 3H), 1.80-1.71 (m, 2H), 1.71-1.59 (m, 1H), 1.28-1.21 (m, 1H), 0.96 (d, J=6.6, 3H).

TABLE 7 depicts intermediates 27-2 and 27-3 were prepared according to Scheme #15 following similar procedures described for Intermediate #27-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 7 Intermediate Structure Compound Name ¹H NMR δ (ppm) 27-2

methyl 4- cyanocyclohex-3-ene- 1-carboxylate ¹H NMR (600 MHz, CDCl₃): δ 6.61-6.57 (m, 1H), 3.68 (s, 3H), 2.62-2.54 (m, 1H), 2.48- 2.40 (m 2H), 2.36-2.22 (m, 2H), 2.10-2.02 (m, 1H), 1.80- 1.70 (m, 1H). 27-3

4,4-dimethylcyclohex- 1-ene-1-carbonitrile ¹H NMR (600 MHz, CDCl₃): δ 6.55-6.52 (m, 1H), 2.24-2.19 (m, 2H), 1.96-1.91 (m, 2H), 1.41 (t, J = 6.4, 2H), 0.91 (s, 6H).

Steps A-B. tert-Butyl 5-cyano-3,6-dihydropyridine-1(2H)-carboxylate

A solution of n-butyllithium (2.8 mL, 7.0 mmol, 2.5 M in hexanes) was added to a solution of diisopropylamine (1.0 mL, 7.0 mmol) in THF (10.0 mL) at 78° C. The cooling bath was removed for 15 minutes, and then the reaction mixture was cooled back to 78° C. A solution of tert-butyl 3-oxopiperidine-1-carboxylate (1.0 g, 5.0 mmol) in THF (6 mL) was added to the cooled solution of LDA dropwise over 5 minutes, maintained for 15 minutes, and then N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (2.4 g, 6.0 mmol) was added in one portion. The reaction mixture was stirred at 78° C. for 15 minutes, and then the cooling bath was removed. The reaction mixture was stirred for 45 minutes after removal of the cooling bath, and was then partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by MPLC on silica gel (using a gradient elution of 0-20%, diethyl ether/hexanes) to afford tert-butyl 5-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate as the second regioisomer to elute. A portion of the product (123 mg, 0.371 mmol) was combined with zinc cyanide (52 mg, 0.45 mmol), Pd(PPh₃)₄ (64 mg, 0.056 mmol) and DMF (1.9 mL) in a microwave tube. The reaction mixture was heated in the microwave at 100° C. for 20 minutes. After cooling to 23° C., the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by MPLC on silica gel (using a gradient elution of 0-100%, EtOAc/hexanes) to afford the title compound.

¹H NMR (500 MHz, CDCl₃): δ 6.73 (br s, 1H), 4.02 (br s, 2H), 3.49 (t, J=5.6 Hz, 2H), 2.29 (br s, 2H), 1.47 (s, 9H).

4-Hydroxycyclohex-1-ene-1-carbonitrile

Step A. 4-Oxocyclohex-1-ene-1-carbonitrile

In a sealed tube, {[(3E)-4-methoxybuta-1,3-dien-2-yl]oxy}(trimethyl)silane (5.65 mL, 29.0 mmol) and acrylonitrile (1.91 mL, 29.0 mmol) were combined in benzene (9.67 mL), heated to reflux, and allowed to stir for 16 hours. The reaction mixture was then cooled to ambient temperature and the volatiles were removed in vacuo (23° C. water bath). The residue was stirred into a mixture of 1N aqueous HCl (29.0 mL, 29.0 mmol) and THF (9.67 mL). After being stirred at ambient temperature for 3 hours, the reaction mixture was extracted with diethyl ether. The organic layer was washed with de-ionized water (2×), brine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo (23° C. water bath). The residue was purified by MPLC on silica gel (using a gradient elution of 0-50% hexanes/acetone). Desired fractions were identified, combined and concentrated in vacuo (23° C. water bath) to afford the title compound.

¹H NMR (600 MHz, CDCl₃): δ 6.68 (tt, J=4.0, 1.5, 1H), 3.05 (dt, J=4.3, 2.2, 2H), 2.71 (tq, J=6.9, 1.9, 2H), 2.61-2.53 (t, J=6.9 2H).

Step B. 4-Hydroxycyclohex-1-ene-1-carbonitrile

To a stirred solution of 4-oxocyclohex-1-ene-1-carbonitrile (170 mg, 1.40 mmol) in MeOH (2.3 mL) at −78° C. was added cerium (III) chloride (484 mg, 1.96 mmol) in MeOH (4.7 mL). The resulting mixture was allowed to stir for 5 minutes at −78° C. before NaBH₄ (48 mg, 1.26 mmol) was added in one portion. The mixture was stirred for 20 minutes and then allowed to warm to ambient temperature. After being stirred for 30 minutes, the reaction mixture was diluted with water and extracted with diethyl ether (3×). The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo (23° C. water bath) to afford the title compound.

¹H NMR (600 MHz, CDCl₃): δ 6.50 (tt, J=3.9, 1.8, 111), 4.03-3.98 (m, 1H), 3.50-3.42 (qd, J=11.4, 4.5, 1H), 2.50 (br d, J=19.2, 1H), 2.46-2.38 (m, 1H), 2.33-2.23 (m, 1H), 2.21-2.13 (m, 1H), 1.90-1.84 (m, 1H), 1.76-1.67 (m, 1H).

1,4-Dioxaspiro[4.5]dec-7-ene-8-carbonitrile

Step A-C. (1R,2S and 1S,2R)-4-Oxo-2-(phenylsulfonyl)cyclohexanecarbonitrile

Benzenesulfinic acid sodium salt (9.4 g, 57 mmol) was dissolved in a mixture of water (18.3 mL) and acetic acid (9.1 mL). 2-Chloroprop-2-enenitrile (4.6 mL, 57 mmol) was added, followed by MeOH (18.3 mL). The resulting mixture was allowed to stir for 10 minutes before the solid product was collected by filtration and rinsed with minimal water. The majority of the solid filtered through with the rinse and so all material was rinsed through the filter. The filtrate was extracted with DCM (2×) and the combined organic layers were washed with saturated aqueous NaHCO₃, brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to afford 2-chloro-3-(phenylsulfonyl)propanenitrile as a crude residue. Crude 2-chloro-3-(phenylsulfonyl)propanenitrile (6.1 g, 27 mmol) was dissolved in chloroform (41 mL) cooled in an ice-salt bath and stirred before adding TEA (3.7 mL, 27 mmol) dropwise. The mixture was allowed to stir at 0° C. for 20 minutes. The reaction mixture was then washed sequentially with dilute 1N aqueous HCl, followed by saturate aqueous NaHCO₃. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo (23° C. water bath) to afford (2E and 2Z)-3-(phenylsulfonyl)prop-2-enenitrile as a crude residue. The crude residue (4.9 g, 25 mmol) and (buta-1,3-dien-2-yloxy)(trimethyl)silane (4.2 g, 29 mmol) were refluxed together in benzene (63.8 mL) under nitrogen for 16 hours. The reaction mixture was then concentrated in vacuo to afford an oily mixture of the intermediate adducts. The residue was dissolved in aqueous acetic acid (80%) and allowed to stir. After 1 hour at ambient temperature, the mixture was diluted with water and extracted with DCM (2×). The combined organic extracts were concentrated in vacuo and the residue was dissolved in DCM. A solid precipitated from the solution and was collected by filtration to afford the title compound.

¹H NMR (600 MHz, CDCl₃): δ 7.91 (d, J=7.7, 2H), 7.74 (t, J=7.4, 1H), 7.63 (t, J=7.8, 2H), 3.81 (q, J=4.4, 1H), 3.68 (q, J=4.8, 1H), 2.76 (dd, J=16.5, 6.3, 1H), 2.74-2.66 (m, 1H), 2.62 (dd, J=11.4, 4.5, 1H), 2.61-2.56 (m, 2H), 2.25 (dq, J=14.3, 4.9, 1H).

Step D-E. 1,4-Dioxaspiro[4.5]dec-7-ene-8-carbonitrile (Intermediate #30)

To a pressure vessel was added (1R,2S and 1S,2R)-4-oxo-2-(phenylsulfonyl) cyclohexanecarbonitrile (100 mg, 0.380 mmol), benzene (19.0 mL), ethylene glycol (0.90 mL, 16 mmol), and p-toluenesulfonic acid monohydrate (14 mg, 0.076 mmol). The vessel was capped and the reaction mixture was heated to reflux and allowed to stir for 16 hours. The reaction mixture was allowed to cool to ambient temperature before it was diluted with EtOAc. The organic layer was washed with water (3×), brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo (23° C. water bath) to afford (7S,8R and 7R,8S)-7-(phenylsulfonyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile as a crude residue. To the crude residue (110 mg, 0.358 mmol) was added THF (7.1 mL) and potassium tert-butoxide (137 mg, 1.22 mmol). The reaction mixture was allowed to stir at ambient temperature for 15 minutes before it was diluted with diethyl ether. The organic layer was washed with water, brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo (23° C. water bath) to afford the title compound.

¹H NMR (600 MHz, CDCl₃): δ 6.48 (tt, J=4.0, 1.8, 1H), 3.96 (s, 4H), 2.45 (tq, J=6.6, 2.2, 2H), 2.39 (q, J=3.1, 2H), 1.78 (t, J=6.6, 2H).

3-(Phenylamino)-1H pyrazole-4-carboxamide

3-Amino-1H-pyrazole-4-carboxamide (19.8 g, 157 mmol), K₃PO₄ (66.7 g, 314 mmol), bromobenzene (23.2 mL, 220 mmol) and 2-propanol (785 mL) were combined in a round bottom flask and purged with a stream of N₂ gas for 40 minutes. Pd₂(dba)₃ (1.80 g, 1.96 mmol) and 2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-i-propylbiphenyl (3.77 g, 7.85 mmol) were added and the reaction was purged for an additional 5 minutes. The reaction mixture was then heated to 80° C. and allowed to stir under a N₂ atmosphere for 12 hours. The mixture was then allowed to cool to ambient temperature for an additional 16 hours. The reaction mixture was diluted with EtOAc (300 mL) and filtered through celite (slowly). The celite was washed with EtOAc (300 mL) and the combined filtrates were concentrated in vacuo to afford an oil which was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM). The major, low rf product, was isolated to afford a reddish-brown oily solid. The brown solid was suspended in 40 mL of warm MeOH, cooled to ambient temperature, and water (40 mL) was added. The mixture was stirred for 30 minutes and filtered. The solid was suction dried for 16 hours to afford the title compound as a peach-colored solid.

LRMS (ESI) calc'd for C₁₀H₁₀N₄O [M+H]⁺: 203. Found: 203.

The following intermediates shown in TABLE 8 were prepared according to Scheme #19 following similar procedures described for Intermediate #31-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 8 Exact Mass Intermediate Structure Compound Name [M + H]⁺ 31-2

3-[(4-bromophenyl)amino]- 1H-pyrazole-4-carboxamide Calc'd 280, Found 280 31-3

3-({4- [(trifluoromethyl)sulfanyl]- phenyl}amino)-1H-pyrazole-4- carboxamide Calc'd 303, Found 303 31-4

3-{[3-(1H-imidazol-1- ylmethyl)phenyl]amino}-1H- pyrazole-4-carboxamide Calc'd 283, Found 283 31-5

3-[(3-{[4-(2-hydroxypropan-2- yl)-1H-1,2,3-triazol-1- yl]methyl}phenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 342, Found 342 31-6

3-{[3-(1H-benzotriazol-1- ylmethyl)phenyl]amino}-1H- pyrazole-4-carboxamide Calc'd 334, Found 334 31-7

3-[(4-fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 221, Found 221 31-8

3-[(6-fluoropyridin-3- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 222, found 222

3-({4-[(trifluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide

The title compound, Intermediate #32, can be prepared according to the general procedure described for Intermediate #31-1 using 3-amino-1H-pyrazole-4-carboxamide (0.48 g, 3.8 mmol) and 1-bromo-4-[(trifluoromethyl)sulfonyl]benzene (1.0 g, 3.5 mmol) as starting materials.

LRMS (ESI) calc'd for C₁₇H₁₈FN₅O₂ [M+H]⁺: 335. Found: 335.

Alternatively, the title compound, Intermediate #32, can also be prepared by dissolving 3-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)-1H-pyrazole-4-carboxamide (Intermediate 31-3) (0.50 g, 1.6 mmol) in acetic acid (5.0 mL) followed by the addition of hydrogen peroxide (0.87 mL, 9.9 mmol, 35 wt % in water). The resulting mixture was heated to 50° C. for 18 hours before additional hydrogen peroxide (0.87 mL, 9.9 mmol, 35 wt % in water) was added and the mixture was heated to 80° C. for 8 hours. The mixture was cooled to ambient temperature, concentrated in vacuo and diluted with EtOAc. The mixture was washed three times with aqueous sodium thiosulfate adjusted to pH>8 with saturated aqueous bicarbonate. The organic layer was collected, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by MPLC on silica gel (15% MeOH/DCM). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.

LRMS (ESI) calc'd for C₁₁H₉F₃N₄O₃S [M+H]⁺: 335. Found: 335.

Propan-2-yl 4-[(4-carbamoyl-1H-pyrazol-3-yl)amino]benzoate

A round-bottomed flask was charged with 2-propanol (595 mL), and nitrogen was bubbled through the 2-propanol for 2 hours. Pd₂(dba)₃ (1.63 g, 1.78 mmol) and di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine (3.43 g, 7.14 mmol) were added, and the mixture was stirred for 20 minutes. Potassium acetate (17.5 g, 178 mmol), 3-amino-1H-pyrazole-4-carboxamide (15.0 g, 119 mmol), and isopropyl 4-bromobenzoate (34.7 g, 143 mmol) were then added, and the reaction mixture was heated to 75° C. for 6.5 hours. The reaction mixture was then cooled to 23° C., diluted with EtOAc (500 mL), and filtered through celite. The filtrate was adsorbed onto silica gel in vacuo and purified by MPLC on silica gel (using a gradient elution of 30-90%, EtOAc/hexanes) to afford the title compound.

LRMS (ESI) calc'd for C₁₄H₁₇N₄O₃ [M+H]⁺: 289. Found: 289.

3-(Pyridin-4-ylamino)-1H-pyrazole-4-carboxamide

Step A. 3-Amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile and 5-Amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile

3-Amino-1H-pyrazole-4-carbonitrile (10 g, 93 mmol) and NaH (4.0 g, 100 mmol, 60% dispersion in oil) were suspended in DMF (60 mL) at 0° C. SEMCl (19.7 mL, 111 mmol) was added dropwise and the resulting mixture was maintained at ambient temperature for 16 hours. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Purification of the residue by MPLC on silica gel gave a mixture of two regioisomers as a yellow oily solid. 3-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile and 5-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile

¹H NMR (600 MHz, DMSO-d₆):

7.54 (s, 1H), 6.77 (s, 2H), 5.21 (s, 2H), 3.49 (m, 2H), 0.78 (m, 2H), 0.08 (s, 9H). ¹H NMR (600 MHz, DMSO-d₆): δ 8.24 (s, 1H), 5.60 (s, 2H), 5.11 (s, 2H), 3.47 (m, 2H), 0.79 (m, 2H), 0.07 (s, 9H).

Step B. 3-(Pyridin-4-ylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile and 5-(pyridin-4-ylamino)-1-{[2-(trimethylsilyl)ethoxyl]methyl}-1H-pyrazole-4-carbonitrile

To a microwave vessel was added a mixture of 3-amino-1-{[2-(trimethylsilyl) ethoxy]methyl}-1H-pyrazole-4-carbonitrile and 5-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (500 mg, 2.1 mmol), 4- iodopyridine (0.52 g, 2.5 mmol), dioxane (10.5 mL) and K₃PO₄ (0.89 g, 4.2 mmol). The mixture was degassed by bubbling nitrogen gas for 5 minutes. Pd₂(dba)₃ (0.19 mg, 0.21 mmol), and X-Phos (0.30 g, 0.63 mmol) were then added, and the mixture was heated to 100° C. and allowed to stir for 14 hours. The mixture was then allowed to cool to ambient temperature and was filtered through celite. The filtrate was adsorbed on silica gel in vacuo and the mixture was purified by MPLC on silica gel (using a gradient elution of 20-100% EtOAc/DCM) to afford the title compounds. LRMS (ESI) calc'd for C₁₅H₂₂N₅OSi [M+H]⁺: 316. Found: 316.

Step C. 3-(Pyridin-4-ylamino)-1H-pyrazole-4-carboxamide

To a solution containing a mixture of 3-(pyridin-4-ylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile and 5-(pyridin-4-ylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (150 mg, 0.5 mmol) in DMSO (1.2 mL) and EtOH (1.2 mL) was added 5M aqueous NaOH (0.7 mL, 3.3 mmol). The mixture was heated to 55° C., followed by the dropwise addition of 30% H₂O₂ (0.7 mL, 7.1 mmol). After 10 minutes, additional 30% H₂O₂ (0.30 mL, 3.4 mmol) was added dropwise. The mixture was maintained for 30 minutes before it was allowed to cool to ambient temperature. To the crude reaction mixture was added MeOH (1 mL) and 6N aqueous HCl (2 mL). The resulting mixture was heated at 55° C. for 1.5 hours. Additional 6N aqueous HCl (1 mL) was added and the mixture continued stirring for another 1 hour. The mixture was cooled to ambient temperature and carefully neutralized with 5N aqueous NaOH until pH 6-7. The mixture was then concentrated in vacuo to remove most of the solvent. To the slurry-like residue was added MeOH (20 mL), and the resulting mixture was sonicated for 5 minutes. The mixture was filtered to remove insoluble precipitate and the filtrate was concentrated in vacuo to afford crude residue containing the title compound, Intermediate #34-1, which was used without further purification.

LRMS (ESI) calc'd for C₉H₉N₅O [M+H]⁺: 204. Found: 204.

The following intermediates shown in TABLE 9 were prepared according to Scheme #20 following similar procedures described for Intermediate #34-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 9 Exact Mass Intermediate Structure Compound Name [M + H]⁺ 34-2

3-{[4-(methylsulfonyl)phenyl]amino}- 1H-pyrazole-4-carboxamide Calc'd 281, Found 281 34-3

3-({4-[(1,1-dioxidothiomorpholin-4- yl)carbonyl]phenyl}amino)-1H-pyrazole- 4-carboxamide Calc'd 364, Found 364

tert-Butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

3-Amino-1H-pyrazole-4-carboxamide (0.80 g, 6.3 mmol) and tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (2.1 g, 9.5 mmol) were combined with acetonitrile (31 mL) in a pressure vessel. DBU (1.05 mL, 6.98 mmol) was then added at ambient temperature. The reaction vessel was sealed and the mixture was heated to 80° C. for 16 hours. The reaction mixture was then allowed to cool to ambient temperature before water (150 mL) was added. The aqueous mixture was extracted with EtOAc (2×). The organic layers were then combined and washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The crude residue was adsorbed on silica gel in vacuo and purified by MPLC on silica gel (using a gradient elution of 75-100% EtOAc/hexanes) to afford the title compound, Intermediate #35-1.

LRMS (ESI) calc'd for C₁₆H₂₄N₆O₃ [M+H]⁺: 349. Found: 349

The following intermediates shown in TABLE 10 were prepared according to Scheme #21 following similar procedures described for Intermediate #35-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 10 Exact Mass Intermediate Structure Compound Name [M + H]⁺ 35-2

3-amino-1-(2-cyano-1- cyclopropylethyl)-1H- pyrazole-4-carboxamide Calc'd 220, Found 220 35-3

2,2,2-trifluoroethyl 4-(3- amino-4-carbamoyl-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 375, Found 375 35-4

2,2-difluoroethyl 4-(3- amino-4-carbamoyl-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 357, Found 357 35-5

3-amino-1-(8- (cyanomethyl)-1,4- dioxaspiro[4.5]decan-8-yl)- 1H-pyrazole-4-carboxamide Calc'd 306, Found 306

3-Amino-1-[(1S,2S and 1R,2R)-2-cyano-4-hydroxycyclohexyl]-1H-pyrazole-4-carboxamide

DBU (1.20 mL, 7.93 mmol) was added to a mixture of 3-amino-1H-pyrazole-4-carboxamide (500 mg, 3.96 mmol) and 5-hydroxycyclohex-1-ene-1-carbonitrile (976 mg, 7.93 mmol) in ethanol (7.2 mL) at 23° C. The reaction mixture was then heated to 70° C. for 16 hours. The mixture was then cooled to ambient temperature, silica gel was added, and the mixture was concentrated in vacuo. The resulting powder was then purified by MPLC on silica gel (using a gradient elution of 0-15%, MeOH/EtOAc) to afford the title compound. The stereochemistry of the major isomer was 1,2-trans, 1,4-cis, and the minor isomer was 1,2-trans, 1,4-trans, with these two isomers constituting 90% of the product mixture. LRMS (ESI) calc'd for C₇H₁₆N₅O₂ [M+H]⁺: 250. Found: 250.

3-Amino-1-[(1S,2S and 1R,2R)-2-cyanocyclohexyl]-1H-pyrazole-4-carboxamide and 3-amino-1-[(1S,2R and 1R,2S)-2-cyanocyclohexyl]-1H-pyrazole-4-carboxamide

The title compounds were prepared according to the general procedure in

Intermediate 36 using 3-amino-1H-pyrazole-4-carboxamide (10 g, 79 mmol) and cyclohex-1-ene-1-carbonitrile (17 g, 160 mmol) as starting materials.

Intermediate #37-1: 3-Amino-1-[(1S,2S and 1R,2R)-2-cyanocyclohexyl]-1H-pyrazole-4-carboxamide

LRMS (ESI) calc'd for C₁₁H₁₆N₅O [M+H]⁺: 234. Found: 234.

Intermediate #37-2: 3-Amino-1-[(1S,2R and 1R,2S)-2-cyanocyclohexyl]-1H-pyrazole-4-carboxamide

LRMS (ESI) calc'd for C₁₁H₁₆N₅O [M+H]⁺: 234. Found: 234.

EXAMPLES OF THE INSTANT INVENTION

The following experimental procedures detail the preparation of specific examples of the instant invention. The examples are for illustrative purposes only and are not intended to limit the scope of the instant invention in any way.

tert-Butyl 4-(cyanomethyl)-4-[4-(methylcarbamoyl)-3-(phenylamino)-1H-pyrazol-1-yl]piperidine-1-carboxylate

Step A. tert-Butyl 4-[3-amino-4-(methoxycarbonyl)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate (Step A Intermediate)

To a flask containing 5-amino-1H-pyrazole-4-carboxylic acid methyl ester (2.0 g, 14 mmol) was added tert-butyl 4-(cyanomethylidene)piperidine-1-carboxylate (6.3 g, 28 mmol), acetonitrile (57 mL), and DMF (25 mL), followed by the addition of catalytic NaOMe (0.10 g, 2.1 mmol). The mixture was heated to 70° C. and allowed to stir for 18 hours. The mixture was then allowed to cool to ambient temperature, diluted with water and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound. LRMS (ESI) calc'd for C₁₇H₂₆N₅O₄ [M+H]⁺: 364. Found: 364.

Step B. tert-Butyl 4-(cyanomethyl)-4-[4-(methoxycarbonyl)-3-(phenylamino)-1H-pyrazol-1-yl]piperidine-1-carboxylate (Step B Intermediate)

To a microwave vessel was added tert-butyl 4-[3-amino-4-(methoxycarbonyl)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate (0.400 g, 1.10 mmol), K₃PO₄ (467 mg, 2.20 mmol), bromobenzene (0.13 mL, 1.2 mmol), and dioxane (5.5 mL). The mixture was degassed by bubbling argon for 5 minutes. Pd₂(dba)₃ (50 mg, 0.05 mmol) and X-Phos (79 mg, 0.16 mmol) were added, and the vial was sealed and heated to 95° C. for 3 hours. The reaction was then cooled to ambient temperature, diluted with EtOAc, filtered through celite, and rinsed with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by MPLC on silica gel (using a gradient elution of 0-50% EtOAc/hexanes) to afford the title compound.

LRMS (ESI) calc'd for C₂₃H₃₀N₅O₄ [M+H]⁺: 440. Found: 440.

Step C. 1-[1-(tert-Butoxycarbonyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxylic acid

To a solution of tert-butyl 4-(cyanomethyl)-4-[4-(methoxycarbonyl)-3-(phenylamino)-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.12 g, 0.27 mmol) in THF (1.8 mL) was added MeOH (1 mL), and 1M aqueous NaOH (0.82 mL, 0.82 mmol). The mixture was heated to 50° C. for 2 hours. The mixture was then cooled to ambient temperature and acidified to pH 3-4 with 1N aqueous HCl. The mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound.

LRMS (ESI) calc'd for C₂₂H₂₈N₅O₄[M+H]⁺: 426. Found: 426.

Step D. Tert-Butyl 4-(cyanomethyl)-4-[4-(methylcarbamoyl)-3-(phenylamino)-1H-pyrazol-1-yl]piperidine-1-carboxylate

To a solution of 1-[1-(tert-butoxycarbonyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxylic acid (25 mg, 0.059 mmol) in DCM (0.6 mL) was added DIPEA (0.030 mL, 0.18 mmol), methylamine (0.040 mL, 0.082 mmol, 2.0 M in THF), HOBT (13 mg, 0.082 mmol), and EDC (16 mg, 0.082 mmol). The resulting mixture was maintained at ambient temperature for 18 hours, then purified directly by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound.

¹H NMR (600 MHz, acetone-d₆): δ 9.19 (s, 1H), 8.33 (s, 1H), 7.54 (d, J=7.2 Hz, 2H), 7.35 (br s, 1H), 7.21 (t, J=7.2 Hz, 2H), 6.79 (t, J=7.2 Hz, 1H), 3.80-3.84 (m, 2H), 3.11 (s, 2H), 3.05 (br s, 2H), 2.83 (s, 3H), 2.52-2.57 (m, 2H), 2.00-2.06 (m, 2H), 1.38 (s, 9H).

LRMS (ESI) calc'd for C₂₃H₃₁N₆O₃ [M+H]⁺: 439. Found: 439.

tert-Butyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate

To a mixture of 3-(phenylamino)-1H-pyrazole-4-carboxamide, Intermediate 31-1, (1.4 g, 6.9 mmol) and tert-butyl 4-(cyanomethylidene)piperidine-1-carboxylate, Intermediate 19-1 (3.1 g, 13.8 mmol) in acetonitrile (23 mL) was added DBU (1.0 mL, 6.9 mmol), and maintained at ambient temperature for 18 hours. The mixture was diluted with water, extracted with EtOAc, and the combined organics were washed with brine, dried over anhydrous MgSO₄, and filtered. The filtrate was adsorbed onto silica gel in vacuo and then purified by MPLC on silica gel (using a gradient elution of 0-80% EtOAc/DCM) to afford the title compound, Example #2-1.

LRMS (ESI) calc'd for C₂₂H₂₈N₆O₃ [M+H]⁺: 425. Found: 425.

¹H NMR (600 MHz, CDCl3): δ 8.78 (s, 1H), 7.76 (s, 1H), 7.51 (d, J=7.2 Hz, 2H), 7.29 (t, J=7.2 Hz, 2H), 6.91 (t, J=7.2 Hz, 1H), 5.48 (br s, 2H), 3.89 (br s, 2H), 3.09-3.14 (m, 2H), 2.90 (s, 2H), 2.59-2.63 (m, 2H), 1.98-2.04 (m, 2H), 1.45 (s, 9H).

The following examples shown in TABLE 11 were prepared according to Scheme #23 following similar procedures described for Example #2-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 11 Exact Mass Example Structure Compound Name [M + H]⁺ 2-2 

tert-butyl 4-{3-[(4- bromophenyl)amino]-4- carbamoyl-1H-pyrazol-1-yl}- 4-(cyanomethyl)piperidine-1- carboxylate Calc'd 503, Found 503 2-3 

tert-butyl 3-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-3-(cyanomethyl)azetidine- 1-carboxylate Calc'd 397, Found 397 2-4 

tert-butyl 4-(3-{[3-(1H- benzotriazol-1- ylmethyl)phenyl]amino}-4- carbamoyl-1H-pyrazol-1-yl)- 4-(cyanomethyl)piperidine-1- carboxylate Calc'd 556, Found 556 2-5 

tert-butyl 3-(4-carbamoyl-3- {[4-(methylsulfonyl)phenyl] amino}-1H-pyrazol-1-yl)-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 475, Found 375 (M + H-Boc) 2-6 

tert-butyl 4-[4-carbamoyl-3- ({4-[(1,1- dioxidothiomorpholin-4- yl)carbonyl]phenyl}amino)- 1H-pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 586, Found 486 (M + H-Boc) 2-7 

tert-butyl 4-[4-carbamoyl-3- (pyridin-4-ylamino)-1H- pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 426, Found 426 2-8 

tert-butyl 3-[4-carbamoyl-3- ({4-[(1,1- dioxidothiomorpholin-4- yl)carbonyl]phenyl}amino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 558, Found 458 (M + H-Boc) 2-9 

tert-Butyl (3S,4R and 3R,4S)-4-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-4-(cyanomethyl)-3- methylpiperidine-1- carboxylate Calc'd 439, Found 439 2-10

tert-Butyl (2S,4R and 2R,4S)-4-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-4-(cyanomethyl)-2- methylpiperidine-1- carboxylate Calc'd 439, Found 439 2-11

tert-butyl (2R,4R and 2S,4S)- 4-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-4-(cyanomethyl)-2- methylpiperidine-1- carboxylate Calc'd 439, Found 439 2-12

1-[3-(cyanomethyl)-1- (ethylsulfonyl)azetidin-3-yl]- 3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 389, Found 389 2-13

1-[3-(cyanomethyl)-1- (ethylsulfonyl)azetidin-3-yl]- 3-({4-[(1,1- dioxidothiomorpholin-4- yl)carbonyl]phenyl}amino)- 1H-pyrazole-4-carboxamide Calc'd 550, Found 550 2-14

1-[1-(cyanomethyl)cyclohexyl]-3- {[4-(methylsulfonyl)phenyl] amino}-1H-pyrazole-4- carboxamide Calc'd 402.0, found 402 2-15

1-[1-(cyanomethyl)cyclohexyl]- 3-(phenylamino)-1H-pyrazole- 4-carboxamide Calc'd 324, found 324 2-16

tert-butyl 3-(4-carbamoyl-3-{[4- (methylsulfonyl)phenyl]amino}- 1H-pyrazol-1-yl)-3- (cyanomethyl)pyrrolidine-1- carboxylate Calc'd 489, found 389 (M + H-Boc) 2-17

tert-butyl 3-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-3-(cyanomethyl)pyrrolidine-1- carboxylate Calc'd 411, found 411 2-18

tert-butyl 4-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-4-(cyanomethyl) cyclohexanecarboxylate Calc'd 424, found 424 2-19

(1s,3s or 1r,3r) tert-butyl {4- [4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-4-(cyanomethyl) cyclohexyl}carbamate Calc'd 439, found 439 2-20

1-[3-(cyanomethyl)oxetan-3- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 298, found 298 2-21

1-((1s,3s)-3-cyano-1- (cyanomethyl)cyclobutyl)-3- (phenylamino)-1H-pyrazole- 4-carboxamide Calc'd 321, found 321 2-22

1-((1r,3r)-3-cyano-1- (cyanomethyl)cyclobutyl)-3- ((4-(methylsulfonyl)phenyl) amino)-1H-pyrazole-4- carboxamide Calc'd 399, found 399 2-23

tert-butyl 6-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-6-(cyanomethyl)-2- azaspiro[3.3]heptane-2- carboxylate Calc'd 437, found 437

1-[4-(Cyanomethyl)-1-(3,4-dimethoxyphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide

[1-(3,4-Dimethoxyphenyl)piperidin-4-ylidene]acetonitrile (Intermediate 25-1) (0.026 g, 0.10 mmol), acetonitrile (0.4 mL), DMF (0.4 mL), 3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide (Intermediate 31-7) (0.022 g, 0.10 mmol), and DBU (0.045 mL, 0.30 mmol) were combined, heated to 50° C., and allowed to stir for 16 hours. The reaction mixture was directly purified by reverse phase preparative HPLC (using a gradient elution of 0-95% MeCN/water, with 0.1% v/v TFA modifier) to afford the title compound, Example #3-1.

LRMS (ESI) calc'd for C₂₅H₂₇FN₆O₃ [M+H]⁺: 479. Found: 479.

¹H NMR (500 MHz, DMSO-d₆): δ 9.05 (s, 1H), 8.52 (s, 1H), 7.62-7.52 (m, 3H), 7.17 (br s, 1H), 7.06 (t, J=8.8 Hz, 2H), 6.81 (d, J=8.8 Hz, 1H), 6.74-6.68 (m, 1H), 6.58-6.50 (m, 1H), 3.72 (s, 3H), 3.66 (s, 3H), 3.50-3.42 (m, 2H), 3.23 (s, 2H), 2.96-2.82 (m, 2H), 2.58-2.46 (m, 2H), 2.28-2.18 (m, 2H).

The following examples shown in TABLE 12 were prepared according to Scheme #23 following similar procedures described for Example #3-1, which can be achieved by those of ordinary skill in the art of organic synthesis utilizing Intermediate 31-7, and intermediates including but not limited to intermediates described in Table 5.

TABLE 12 Exact Mass Example Structure Compound Name [M + H]⁺ 3-2 

1-[4-(cyanomethyl)-1- isoquinolin-4-ylpiperidin-4- yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 470, Found 470 3-3 

1-[4-(cyanomethyl)-1- quinolin-4-ylpiperidin-4-yl]- 3-[(4-fluorophenyl)amino]- 1H-pyrazole-4-carboxamide Calc'd 470, Found 470 3-4 

1-[4-(cyanomethyl)-1-(2- methylpyridin-4-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 434, found 434 3-5 

1-[4-(cyanomethyl)-1-(5- fluoropyridin-3-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 438, found 438 3-6 

1-[4-(cyanomethyl)-1-(2- methoxypyridin-4- yl)piperidin-4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 450, found 450 3-7 

1-{4-(cyanomethyl)-1-[6-(1- hydroxy-1- methylethyl)pyridin-2- yl]piperidin-4-yl}-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 478, found 478 3-8 

1-{4-(cyanomethyl)-1-[5- (trifluoromethyl)pyridin-3- yl]piperidin-4-yl}-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 488, found 488 3-9 

1-{4-(cyanomethyl)-1-[4- (2,2,2-trifluoro-1- hydroxyethyl)phenyl] piperidin-4-yl}-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 517, found 517 3-10

1-{4-(cyanomethyl)-1-[6-(2- hydroxyethoxy)pyridin-2- yl]piperidin-4-yl}-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 480, found 480 3-11

1-[4-(cyanomethyl)-1-(4- fluoro-3-methoxyphenyl) piperidin-4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 467, found 467 3-12

1-[4-(cyanomethyl)-1-(3- fluoro-5- methoxyphenyl)piperidin-4- yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 467, found 467 3-13

1-{4-(cyanomethyl)-1-[6- (difluoromethoxy)pyridin-3- yl]piperidin-4-yl}-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 486, found 486 3-14

1-[4-(cyanomethyl)-1-(5,6- dimethylpyridin-3- yl)piperidin-4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 448, found 488 3-15

1-{4-(cyanomethyl)-1-[6-(1- methylethoxy)pyridin-2- yl]piperidin-4-yl}-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 478, found 478 3-16

1-[4-(cyanomethyl)-1-(6- ethoxypyridin-2-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 464, found 464 3-17

1-[4-(cyanomethyl)-1-(3- cyclopropylphenyl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 459, found 459 3-18

1-[4-(cyanomethyl)-1-(6- cyanopyridin-2-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 445, found 445 3-19

1-{4-(cyanomethyl)-1-[5- (difluoromethoxy)pyridin-2- yl]piperidin-4-yl}-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 486, found 486 3-20

1-[4-(cyanomethyl)-1-(6- methylpyridin-2-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 434, found 434 3-21

1-[4-(cyanomethyl)-1-(5- cyanopyridin-3-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 445, found 445 3-22

1-[4-(cyanomethyl)-1-(6- fluoropyridin-3-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 438, found 438 3-23

1-[4-(cyanomethyl)-1-(3- methoxypyridin-2- yl)piperidin-4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 450, found 450 3-24

1-[4-(cyanomethyl)-1- pyrimidin-5-ylpiperidin-4- yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 421, found 421 3-25

1-[4-(cyanomethyl)-1-(2- methoxypyrimidin-5- yl)piperidin-4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 451, found 451 3-26

1-[4-(cyanomethyl)-1-(4- cyanophenyl)piperidin-4-yl]- 3-[(4-fluorophenyl)amino]- 1H-pyrazole-4-carboxamide Calc'd 444, found 444 3-27

1-[4-(cyanomethyl)-1-(3- fluorophenyl)piperidin-4-yl]- 3-[(4-fluorophenyl)amino]- 1H-pyrazole-4-carboxamide Calc'd 437, found 437 3-28

1-{4-(cyanomethyl)-1-[6- (trifluoromethyl)pyridin-3- yl]piperidin-4-yl}-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 488, found 488 3-29

1-[4-(cyanomethyl)-1-(2- methylpyridin-3-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 434, found 434 3-30

1-[4-(cyanomethyl)-1- pyridin-3-ylpiperidin-4-yl]-3- [(4-fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 420, found 420 3-31

1-[4-(cyanomethyl)-1-(4- methylpyridin-2-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 434, found 434 3-32

1-[4-(cyanomethyl)-1-(5- fluoro-2- methylphenyl)piperidin-4- yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 451, found 451 3-33

1-[4-(cyanomethyl)-1-(4- methylpyridin-3-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 434, found 434 3-34

1-[4-(cyanomethyl)-1-(3- fluoro-4- methylphenyl)piperidin-4- yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 451, found 451 3-35

methyl 6-[4-{4-carbamoyl-3- [(4-fluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidin-1- yl]pyridine-2-carboxylate Calc'd 478, found 478 3-36

1-[4-(cyanomethyl)-1-(6- ethoxypyridin-3-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 464, found 464 3-37

1-[4-(cyanomethyl)-1-(5- methoxypyridin-3- yl)piperidin-4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 450, found 450 3-38

1-[4-(cyanomethyl)-1-(4- fluorophenyl)piperidin-4-yl]- 3-[(4-fluorophenyl)amino]- 1H-pyrazole-4-carboxamide Calc'd 437, found 437 3-39

1-[4-(cyanomethyl)-1-(4- methylphenyl)piperidin-4- yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 433, found 433 3-40

1-[4-(cyanomethyl)-1-(3,5- difluorophenyl)piperidin-4- yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 455, found 455 3-41

1-[4-(cyanomethyl)-1-(2- methoxyphenyl)piperidin-4- yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 449, found 449 3-42

1-[4-(cyanomethyl)-1-(4- fluoro-3- methylphenyl)piperidin-4- yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 451, found 451 3-43

1-[4-(cyanomethyl)-1-(2- fluoro-3- methylphenyl)piperidin-4- yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 451, found 451 3-44

1-[4-(cyanomethyl)-1-(4- fluoropyridin-2-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 438, found 438 3-45

1-[4-(cyanomethyl)-1-(3,4- difluorophenyl)piperidin-4- yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 455, found 455 3-46

1-[4-(cyanomethyl)-1- pyridin-4-ylpiperidin-4-yl]-3- [(4-fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 420, found 420 3-47

1-[4-(cyanomethyl)-1-(4- methylpyrimidin-5- yl)piperidin-4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 435, found 435 3-48

1-[4-(cyanomethyl)-1-(5- methylpyridin-3-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 434, found 434 3-49

1-{4-(cyanomethyl)-1-[6-(2- hydroxy-2- methylpropyl)pyridin-2- yl]piperidin-4-yl}-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 492, found 492 3-50

1-{4-(cyanomethyl)-1-[6- (fluoromethyl)pyridin-2- yl]piperidin-4-yl}-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 452, found 452 3-51

1-[4-(cyanomethyl)-1-(2- fluoropyridin-3-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 438, found 438 3-52

1-[4-(cyanomethyl)-1-(6- methylpyridin-3-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 434, found 434 3-53

1-[4-(cyanomethyl)-1-(6- methoxypyridin-3- yl)piperidin-4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 450, found 450 3-54

1-[4-(cyanomethyl)-1-(6- fluoropyridin-2-yl)piperidin- 4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 438, found 438 3-55

1-{4-(cyanomethyl)-1-[4- (trifluoromethyl)pyridin-2- yl]piperidin-4-yl}-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 488, found 488 3-56

1-[4-(cyanomethyl)-1-(6- fluoro-5-methylpyridin-3- yl)piperidin-4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 452, found 452

tert-Butyl 4-(4-carbamoyl-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

DBU (0.118 mL, 0.785 mmol) was added 3-((4-(methylsulfonyl)phenyl)amino)-1H-pyrazole-4-carboxamide (Intermediate 34-2) (200 mg, 0.714 mmol) and tert-butyl 4-(cyanomethylidene)piperidine-1-carboxylate (Intermediate 19-1) (317 mg, 1.43 mmol) stirred in DMF (3 mL) and the mixture was heated to 50° C. for 5 h. The reaction mixture was cooled to 23° C., water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The combined organic fractions were dried (Na₂SO₄), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexanes to afford the title compound.

LRMS (ESI) calc'd for C₂₃H₃₀N₆O_(5S) [M+H]⁺: 503. Found: 403 [M+H-Boc].

¹H NMR (600 MHz, DMSO-d₆): δ 9.51 (s, 1H), 8.51 (s, 1H), 7.72 (s, 4H), 7.61 (s, 1H), 7.26 (s, 1H), 3.70-3.64 (m, 2H), 3.19 (s, 2H), 3.09 (s, 3H), 3.04-2.94 (m, 2H), 2.37-2.32 (m, 2H), 1.99-1.95 (m, 2H), 1.36 (s, 9H).

The following examples shown in TABLE 13 were prepared according to Scheme #23 following similar procedures described for Examples #4-1, which can be achieved by those of ordinary skill in the art of organic synthesis utilizing, among others, Intermediates 19-1, 19-23, 24, 31-4, 31-6, 33, and 34-2.

TABLE 13 Exact Mass Example Structure Compound Name [M + H]⁺ 4-2

tert-butyl 4-[4-carbamoyl-3- ({4-[(1- methylethoxy)carbonyl]phenyl} amino)-1H-pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 511, Found 511 4-3

tert-butyl 4-(4-carbamoyl-3- {[3-(1H-imidazol-1- ylmethyl)phenyl]amino}-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 505, Found 505 4-4

2,2,2-trifluoroethyl 4-(3-{[3- (1H-benzotriazol-1- ylmethyl)phenyl]amino}-4- carbamoyl-1H-pyrazol-1-yl)- 4-(cyanomethyl)piperidine-1- carboxylate Calc'd 582, Found 582 4-5

1-[4-(cyanomethyl)tetrahydro- 2H-pyran-4-yl]-3-{[4- (methylsulfonyl)phenyl]amino}- 1H-pyrazole-4-carboxamide Calc'd 404, found 404 4-6

tert-butyl 4-{4-carbamoyl-3- [(2-cyanopyrimidin-5- yl)amino]-1H-pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 452, found 396 (loss of t- butyl)

tert-Butyl 4-(4-carbamoyl-3-((4-fluorophenyl)amino)-1H-pyrazol-1-yl)-4-(1-cyanoethyl)piperidine-1-carboxylate

A mixture of tert-butyl 4-(1-cyanoethylidene)piperidine-1-carboxylate (Intermediate 21) (440 mg, 0.020 mol), DBU (0.9 g, 0.006 mol) and 3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide (Intermediate 31-7) (0.5 g, 0.002 mol) in 10 mL of MeCN was stirred under reflux overnight. After the conversion was stable, the mixture was concentrated and purified by reverse phase preparative HPLC (using a gradient elution of 0-95% MeCN/water, with 0.1% v/v TFA modifier) to afford the title compound.

¹H NMR (300 MHz, CDCl₃): δ 6.99-6.93 (m, 2H), 5.69 (s, 2H), 4.08 (s, 2H), 2.86-2.58 (m, 5H), 2.16-2.04 (m, 2H), 1.42 (s, 5H), 0.77 (s, 2H), 0.58 (s, 2H), 0.30 (s, 1H), 0.17 (s, 1H).

The following examples shown in TABLE 14 were prepared according to Scheme #23 following similar procedures described for Example #5-1, which can be achieved by those of ordinary skill in the art of organic synthesis utilizing, among others, Intermediates 19-23, 20, 22, 30, 31-1, 31-7, 31-8, and 34-2.

TABLE 14 Exact Mass Example Structure Compound Name [M + H]⁺ 5-2

tert-butyl 4-{4-carbamoyl-3-[(4- fluorophenyl)amino]-1H-pyrazol- 1-yl}-4- [cyano(cyclopropyl)methyl] piperidine-1-carboxylate Calc'd 483, Found 483 6-3

tert-butyl (3S,4R and 3R,4S)-4- {4-carbamoyl-3-[(4- fluorophenyl)amino]-1H-pyrazol- 1-yl}-4-(cyanomethyl)-3- fluoropiperidine-1-carboxylate Calc'd 461, Found 461 6-4

tert-butyl (3S,4S and 3R,4R)-4- {4-carbamoyl-3-[(4- fluorophenyl)amino]-1H-pyrazol- 1-yl}-4-(cyanomethyl)-3- fluoropiperidine-1-carboxylate Calc'd 461, Found 461 6-5

1-[4-(cyanomethyl)tetrahydro- 2H-pyran-4-yl]-3-(phenylamino)- 1H-pyrazole-4-carboxamide Calc'd 326, found 326 6-6

1-[8-(cyanomethyl)-1,4- dioxaspiro[4.5]dec-8-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 400, found 400 6-7

1-[8-(cyanomethyl)-1,4- dioxaspiro[4.5]dec-8-yl]-3-{[4- (methylsulfonyl)phenyl]amino}- 1H-pyrazole-4-carboxamide Calc'd 460, found 460

1-(4-(Cyanomethyl)tetrahydro-2H-thiopyran-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide

Step A 2-(Dihydro-2H-thiopyran-4(3H)-ylidene)acetonitrile

Potassium tert-butoxide (4.5 mL, 4.5 mmol, 1.0 M in THF) was stirred at 0° C. and THF (10 mL) was added. Diethyl (cyanomethyl)phosphonate (0.72 mL, 4.5 mmol) was added slowly by syringe. The reaction mixture was maintained at 0° C. for 10 minutes, then warmed to ambient temperature and maintained for 1 hour. The mixture was cooled to 0° C. and treated with the dropwise addition of dihydro-2H-thiopyran-4(3H)-one (0.50 g, 4.3 mmol) in THF (7 mL). After addition, the mixture was maintained at 0° C. for 20 minutes, then warmed to ambient temperature and maintained for 18 hours. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified MPLC on silica gel (using a gradient elution of 0-50% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to the title compound.

¹H NMR (500 MHz, CDCl₃): δ 5.15 (s, 1H), 2.83-2.84 (m, 2H), 2.74-2.75 (m, 4H), 2.59 (t, J=5.8 Hz, 2H).

Step B: 1-(4-(Cyanomethyl)tetrahydro-2H-thiopyran-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide

3-[(4-Fluorophenyl)amino]-1H-pyrazole-4-carboxamide (Intermediate 31-7) (100 mg, 0.45 mmol) was added to a mixture of 2-(1,1-dioxidodihydro-2H-thiopyran-4(3H)-ylidene)acetonitrile (160 mg, 0.91 mmol) in MeCN (1.51 mL). DBU (0.068 mL, 0.45 mmol) was then added, the reaction vessel was capped and the reaction mixture was heated to 80° C. for 4 hours. The reaction mixture was cooled to ambient temperature, and purified by reverse phase preparative HPLC (using a gradient elution of MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were combined, basified with saturated aqueous NaHCO₃, and extracted with EtOAc. The organic layer was dried over anhydrous NaSO₄, filtered, and concentrated in vacuo to afford the title compound, Example #7.

LRMS (ESI) calc'd for C₁₇H₁₈FN₅OS [M+H]⁺: 360. Found: 360.

¹H NMR (500 MHz, 10:1 CDCl₃:CD₃OD): δ 8.09 (s, 1H), 7.37-7.38 (m, 2H), 6.89 (t, J=8.7 Hz, 2H), 2.76-2.85 (m, 4H), 2.67-2.70 (m, 2H), 2.53 (d, J=14.4 Hz, 2H), 2.13 (ddd, J=14.2, 11.0, 3.3 Hz, 2H).

1-(4-(Cyanomethyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide

Step A: 2-(1,1-Dioxidodihydro-2H-thiopyran-4(3H)-ylidene)acetonitrile

Potassium tert-butoxide (3.5 mL, 3.5 mmol, 1.0 M in THF) was stirred at 0° C. and THF (8 mL) was added. Diethyl (cyanomethyl)phosphonate (0.56 mL, 3.5 mmol) was added slowly by syringe. The reaction mixture was maintained at 0° C. for 10 minutes, then warmed to ambient temperature and maintained for 1 hour. The mixture was cooled to 0° C. and treated with the dropwise addition of dihydro-2H-thiopyran-4(3H)-one 1,1-dioxide (0.50 g, 3.4 mmol) in THF (5 mL). After addition, the mixture was maintained at 0° C. for 20 minutes, then warmed to ambient temperature and maintained for 18 hours. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified MPLC on silica gel (using a gradient elution of 0-50% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to the title compound.

Step B: 1-(4-(Cyanomethyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide

3-[(4-Fluorophenyl)amino]-1H-pyrazole-4-carboxamide (Intermediate 31-7) (100 mg, 0.45 mmol) was added to a mixture of 2-(dihydro-2H-thiopyran-4(3H)-ylidene)acetonitrile (130 mg, 0.91 mmol) in MeCN (1.51 mL). DBU (0.068 mL, 0.45 mmol) was then added, the reaction vessel was capped and the reaction mixture was heated to 80° C. for 4 hours. The reaction mixture was cooled to ambient temperature, and purified by reverse phase preparative HPLC (using a gradient elution of MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were combined, basified with saturated aqueous NaHCO₃, and extracted with EtOAc. The organic layer was dried over anhydrous NaSO₄, filtered, and concentrated in vacuo to afford the title compound, Example #8.

LRMS (ESI) calc'd for C₁₇H₁₈FN₅O₃S [M+H]⁺: 392. Found: 392.

¹H NMR (500 MHz, 10:1 CDCl₃:CD₃OD): δ 8.24 (s, 1H), 7.33-7.34 (m, 2H), 6.89 (t, J=8.6 Hz, 2H), 2.97-3.10 (m, 6H), 2.86 (s, 2H), 2.53-2.56 (m, 2H).

tert-Butyl 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate

To a microwave vial was added tert-butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (Intermediate 35-1) (5.0 g, 14 mmol), 4-bromo-2-fluoropyridine (2.5 g, 14 mmol), K₃PO₄ (6.1 g, 29 mmol), and dioxane (72 mL). The mixture was degassed with bubbling argon for 5 minutes. Pd₂(dba)₃ (0.7 g, 0.7 mmol) and X-Phos (1.0 g, 2.2 mmol) were then added, and the vial was sealed and heated to 95° C. for 5 hours. The mixture was then cooled to ambient temperature, diluted with EtOAc, filtered through celite, and eluted with EtOAc. The filtrate was concentrated in vacuo, and the resulting yellow oil was purified by MPLC on silica gel (using a gradient elution of 50-100% EtOAc/hexanes) to afford the title compound, Example #9-1.

LRMS (ESI) calc'd for C₂₁H₂₆FN₇O₃ [M+H]⁺: 444. Found: 444.

¹H NMR (500 MHz, acetone-d₆): δ 9.78 (s, 1H), 8.56 (s, 1H), 7.95 (d, J=5.6 Hz, 1H), 7.41 (d, J=1.5 Hz, 1H), 7.38-7.24 (m, 2H), 6.69 (br s, 1H), 3.92-3.84 (m, 2H), 3.23 (s, 2H), 3.15 (br s, 2H), 2.61 (d, J=14.2 Hz, 2H), 2.20-2.10 (m, 2H), 1.44 (s, 9H).

The following examples, disclosed in TABLE 15 were prepared according to Scheme #24 following similar procedures described for Example #9-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 15 Exact Mass Example Structure Compound Name [M + H]⁺ 9-2 

tert-butyl 4-(4-carbamoyl-3-{[4- (methoxycarbonyl)phenyl]amino}- 1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 483, Found 483 9-3 

tert-butyl 4-{4-carbamoyl-3-[(4- fluorophenyl)amino]-1H-pyrazol- 1-yl}-4-(cyanomethyl)piperidine- 1-carboxylate Calc'd 443, Found 443 9-4 

tert-Butyl 4-[4-(aminocarbonyl)-3- ({4-[(methylamino)carbonyl] phenyl}amino)-1H-pyrazol-1-yl]- 4-(cyanomethyl)piperidine-1- carboxylate Calc'd 482, Found 482 9-5 

tert-butyl 4-{4-carbamoyl-3-[(4- cyanophenyl)amino]-1H-pyrazol- 1-yl}-4-(cyanomethyl)piperidine- 1-carboxylate Calc'd 450, Found 450 9-6 

tert-butyl 4-(4-carbamoyl-3-(6-(2- hydroxypropan-2-yl)pyridin-3- ylamino)-1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 484, Found 484 9-7 

tert-butyl 4-(4-carbamoyl-3-(6-(1- hydroxyethyl)pyridin-3-ylamino)- 1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 470, Found 470 9-8 

tert-butyl 4-(4-carbamoyl-3-(4-(2- hydroxypropan-2-yl)phenylamino)- 1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 483, Found 465 (M—OH) 9-9 

tert-butyl 4-(4-carbamoyl-3-(4-(1- hydroxyethyl)phenylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 469, Found 451 (M—OH) 9-10

tert-butyl 4-(3-(4- acetylphenylamino)-4-carbamoyl- 1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 467, Found 467 9-11

tert-butyl 4-(4-carbamoyl-3-{[4- (trifluoroacetyl)phenyl]amino}- 1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 521, Found 521 9-12

tert-butyl 4-{4-carbamoyl-3-[(6- cyanopyridin-3-yl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 451, Found 451 9-13

tert-butyl 4-(4-carbamoyl-3-{[4-(1- methyl-1H-pyrazol-3- yl)phenyl]amino}-1H-pyrazol-1- yl)-4-(cyanomethyl)piperidine-1- carboxylate Calc'd 505, Found 505 9-14

tert-butyl 4-{3-[(2-aminopyridin-4- yl)amino]-4-carbamoyl-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 441, Found 441 9-15

tert-butyl 4-[4-carbamoyl-3-({4- [(trifluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 557, Found 501 (M + H—C₄H₈) 9-16

tert-butyl 4-[4-carbamoyl-3-({4- [(difluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 539, Found 483 (M + H—C₄H₈) 9-17

tent-butyl 4-{4-carbamoyl-3-[(2- methylpyridin-4-yl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 440, Found 440 9-18

tert-butyl 4-(4-carbamoyl-3-{[2- (hydroxymethyl)pyridin-4- yl]amino}-1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 456, Found 456 9-19

tert-butyl 4-{4-carbamoyl-3-[(2- methoxypyridin-4-yl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 456, Found 456 9-20

tert-butyl 4-{4-carbamoyl-3-[(4- sulfamoylphenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 504, Found 404 (M + H—Boc) 9-21

tert-butyl 4-(4-carbamoyl-3-{[4- (dimethylsulfamoyl)phenyl]amino}- 1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 532, Found 432 (M + H—Boc) 9-22

tert-butyl 4-(4-carbamoyl-3-{[4- (dimethylcarbamoyl)phenyl]amino}- 1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 443, Found 443 9-23

tert-butyl 4-(4-carbamoyl-3-{[2- (trifluoromethyl)pyridin-4- yl]amino}-1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 494, Found 494 9-24

tert-butyl 4-(4-carbamoyl-3-{[3- fluoro-4-(morpholin-4- ylcarbonyl)phenyl]amino}-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 556, Found 556 9-25

tert-butyl 4-(4-carbamoyl-3-{[4- (morpholin-4- ylcarbonyl)phenyl]amino}-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 538, Found 538 9-26

tert-butyl 4-{4-carbamoyl-3-[(4- cyano-3-fluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 468, Found 468 9-27

tert-butyl 4-{4-carbamoyl-3-[(2- carbamoylpyridin-4-yl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 469, Found 469 9-28

tert-butyl 4-{4-carbamoyl-3-[(3,4- difluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 461, Found 461 9-29

tert-butyl 4-{4-carbamoyl-3-[(2- chloropyridin-4-yl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 460, Found 460 9-30

tert-butyl 4-(4-carbamoyl-3-{[4-(3- methyl-1,2,4-oxadiazol-5- yl)phenyl]amino}-1H-pyrazol-1- yl)-4-(cyanomethyl)piperidine-1- carboxylate Calc'd 507, Found 507 9-31

tert-butyl 4-{4-carbamoyl-3-[(2,6- dichloropyridin-4-yl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 495, Found 495 9-32

tert-butyl 4-(4-carbamoyl-3-{[4-(5- methyl-1,2,4-oxadiazol-3- yl)phenyl]amino}-1H-pyrazol-1- yl)-4-(cyanomethyl)piperidine-1- carboxylate Calc'd 507, Found 507 9-33

tert-butyl 4-{4-carbamoyl-3-[(2- cyanopyridin-4-yl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 451, Found 451 9-34

tert-butyl 4-[4-carbamoyl-3- (pyridin-3-ylamino)-1H-pyrazol-1- yl]-4-(cyanomethyl)piperidine-1- carboxylate Calc'd 426, Found 426 9-35

tert-butyl 4-{4-carbamoyl-3-[(5- fluoropyridin-3-yl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 444, Found 444 9-36

tert-butyl 4-{4-carbamoyl-3-[(5- chloropyridin-3-yl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 460, Found 460 9-37

2,2-difluoroethyl 4-(4-carbamoyl- 3-{[6-(cyclobutyloxy)pyridin-3- yl]amino}-1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 504, found 504 9-38

2,2-difluoroethyl 4-{4-carbamoyl- 3-[(6-cyclobutylpyridin-3- yl)amino]-1H-pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 488, found 488 9-39

2,2-difluoroethyl 4-{4-carbamoyl- 3-[(2-methoxypyridin-4-yl)amino]- 1H-pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 464, found 464 9-40

2,2-difluoroethyl 4-{4-carbamoyl- 3-[(6-cyclopropylpyridin-3- yl)amino]-1H-pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 474, found 474 9-41

2,2-difluoroethyl 4-{4-carbamoyl- 3-[(2-cyclopropylpyridin-4- yl)amino]-1H-pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 474, found 474

2,2,2-Trifluoroethyl 4-(4-carbamoyl-3-(6-(2-hydroxypropan-2-yl)pyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

2-(5-Bromopyridin-2-yl)propan-2-ol (Intermediate 5) (23 mg, 0.11 mmol), 2,2,2-trifluoroethyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (Intermediate 35-3) 40 mg, 0.11 mmol), Pd₂(dba)₃ (10 mg, 0.011 mmol), 2-di-t-butylphosphino-3,4,5,6-teramethyl-2′,4′,6′-triisopropylbiphenyl (15 mg, 0.032 mmol), potassium phosphate (45 mg, 0.21 mmol), and 1,4-dioxane (1.0 mL) were combined in a 4 mL vial. The vial was capped and flushed with argon. The mixture was heated to 90° C. and allowed to stir for 2 hours. The mixture was then cooled to ambient temperature, diluted with EtOAc, and washed sequentially with water and brine. The organic layer was dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound, Example #10-1.

¹H NMR (500 MHz, CDCl3): δ 8.9 (s, 1H), δ 8.8 (d, J=2.4 Hz, 1H), 8.0 (s, 1H), 7.8 (dd, J=2.4 Hz, J=6.4 Hz, 1H), 7.3 (d, J=8.3 Hz, 1H), 5.9 (br s, 2H), 4.9 (s, 1H), 4.5 (m, 2H), 4.02-3.94 (m, 2H), 3.18-3.11 (m, 2H), 2.9 (s, 2H), 2.72-2.64 (m, 2H), 2.05-1.98 (m, 2H), 1.5 (s, 6H).

LRMS (ESI) calc'd for C₂₂H₂₆F₃N₇O₄ [M+H]⁺: 510. Found: 510

The following compounds disclosed in TABLE 16 were prepared according to Scheme #24 following similar procedures described for Example #10-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 16 Exact Mass Example Structure Compound Name [M + H]⁺ 10-2

2,2,2-trifluoroethyl 4-(4- carbamoyl-3-(4- (trifluoromethylsulfonyl) phenylamino)-1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 583, Found 583 10-3

2,2,2-trifluoroethyl 4-(4- carbamoyl-3-(6-(2,2,2-trifluoro- 1-hydroxyethyl)pyridin-3- ylamino)-1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 550, Found 550 10-4

2,2,2-trifluoroethyl 4-(3-(3- (1H-pyrazol-3- yl)phenylamino)-4-carbamoyl- 1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 517, Found 517 10-5

2,2,2-trifluoroethyl 4-(4- carbamoyl-3-(3-(1-methyl-1H- pyrazol-4-yl)phenylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 531, Found 531 10-6

2,2,2-trifluoroethyl 4-(4- carbamoyl-3-(5-(1-methyl-1H- pyrazol-4-yl)pyridinl-3- ylamino)-1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 532, Found 532 10-7

2,2,2-trifluoroethyl 4-(4- carbamoyl-3-(pyridin-3- ylamino)-1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 452, Found 452 10-8

2,2,2-trifluoroethyl 4-(4- carbamoyl-3-(5-fluoropyridin- 3-ylamino)-1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 470, Found 470 10-9

2,2,2-trifluoroethyl 4-{4- carbamoyl-3-[(5-chloropyridin- 3-yl)amino]-1H-pyrazol-1-yl}- 4-(cyanomethyl)piperidine-1- carboxylate Calc'd 486, Found 486

2,2,2-Trifluoroethyl 4-(4-carbamoyl-3-{[6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

Step A: 2,2,2-Trifluoroethyl 4-(4-carbamoyl-3-((6-chloropyridin-3-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

5-Bromo-2-chloropyridine (206 mg, 1.07 mmol), 2,2,2-trifluoroethyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (400 mg, 1.07 mmol), Pd₂(dba)₃ (98 mg, 0.11 mmol), 2-di-t-butylphosphino-3,4,5,6-teramethyl-2′,4′,6′-triisopropylbiphenyl (154 mg, 0.321 mmol), and potassium phosphate (454 mg, 2.14 mmol) were combined in a 40 mL vial and dissolved in 1,4-dioxane (5.3 mL). The vial was capped, flushed with argon, and stirred at 90° C. for 2 hours. The mixture was cooled to ambient temperature and diluted with ethyl acetate. The organic layer was then washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-5% MeOH/DCM) to afford 2,2,2-trifluoroethyl 4-(4-carbamoyl-3-((6-chloropyridin-3-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate.

¹H NMR (500 MHz, Acetone-d₆) δ 9.34 (s, 1H), 8.67-8.67 (d, J=2.9 Hz, 1H), 8.55 (s, 1H), 8.17-8.15 (dd, J=2.9, 8.8 Hz, 1H), 7.31-7.29 (d, J=8.8 Hz, 1H), 7.25 (br, 1H), 6.64 (br, 1H), 4.68-4.63 (m, 2H), 3.98-3.96 (m, 2H), 3.32-3.28 (m, 2H), 3.23 (s, 2H), 2.71-2.69 (m, 2H), 2.23-2.17 (m, 2H).

LRMS (ESI) calc'd for C₁₉H₁₉ClF₃N₇O₃ [M+H]⁺: 486. Found: 486.

Step B: 2,2,2-Trifluoroethyl 4-(4-carbamoyl-3-{[6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

2,2,2-Trifluoroethyl 4-(4-carbamoyl-3-(6-chloropyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (45 mg, 0.093 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (23 mg, 0.11 mmol), Pd(dppf)Cl₂ (8 mg, 0.009 mmol), potassium phosphate (59 mg, 0.28 mmol), 1,4-dioxane (0.25 mL), and water (0.03 mL) were combined in a 4 mL vial. The vial was then sealed and flushed with argon. The mixture was heated to 90° C. and was allowed to stir for 90 minutes. The mixture was cooled to ambient temperature, diluted with EtOAc and washed sequentially with water and brine. The organic layer was dried with anhydrous MgSO₄, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound, Example #11-1.

¹H NMR (500 MHz, CDCl3): δ 8.89 (s, 1H), δ 8.86 (d, J=2.4 Hz, 1H), 7.89 (s, 1H), 7.85 (s, 2H), 7.78 (dd, J=2.4 Hz, J=6.4 Hz, 1H), 7.4 (d, J=8.3 Hz, 1H), 5.7 (br s, 2H), 4.5 (m, 2H), 4.02-3.94 (m, 2H), 3.9 (s, 3H), 3.18-3.11 (m, 2H), 2.9 (s, 2H), 2.72-2.64 (m, 2H), 2.05-1.98 (m, 2H).

LRMS (ESI) calc'd for C₂₃H₂₄F₃N₉O₃ [M+H]⁺: 532. Found: 532.

The following compounds shown in TABLE 17 were prepared following similar procedures described for Example #11-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 17 Exact Mass Example Structure Compound Name [M + H]⁺ 11-2

2,2,2-trifluoroethyl 4-(4- carbamoyl-3-{[6-(1H-pyrazol-4- yl)pyridin-3-yl]amino}-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 518, found 518

tert-Butyl 4-{3-[(3-bromophenyl)amino]-4-carbamoyl-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate

tert-Butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (Intermediate 35-1) (500 mg, 1.44 mmol), potassium acetate (211 mg, 2.15 mmol), 1,3-dibromobenzene (0.69 mL, 5.74 mmol) and 2-propanol (7.2 mL) were combined in a vial and purged with a stream of N₂ gas for 10 minutes. Pd₂(dba)₃ (52 mg, 0.060 mmol) and 2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-i-propylbiphenyl (103 mg, 0.220 mmol) were then added. The reaction vessel was capped and the reaction mixture was heated to 85° C. and allowed to stir for 16 hours. The mixture was then cooled to ambient temperature, filtered through celite, eluting with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound, Example #12-1.

¹H NMR (600 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.52-8.44 (m, 1H), 7.80 (s, 1H), 7.55 (s, 1H), 7.42 (d, J=10.0 Hz, 1H), 7.20 (s, 1H), 7.16 (dd, J=13.7, 21.7 Hz, 1H), 6.97 (d, 1H), 3.67 (d, J=14.0 Hz, 2H), 3.15 (s, 2H), 2.98 (s, 2H), 2.39-2.25 (m, 2H), 1.95 (s, 2H), 1.36 (s, 9H).

LRMS (ESI) calc'd for C₂₂H₂₇BrN₆O₃ [M+H− tert-butyl]⁺: 448. Found: 448.

The following compounds shown in TABLE 18 were prepared according to Scheme #24 following similar procedures described for Example #12-1, which can be achieved by those of ordinary skill in the art of organic synthesis utilizing but not limited to Intermediate 35-1.

TABLE 18 Exact Mass Example Structure Compound Name [M + H]⁺ 12-2

tert-butyl 4-(4-carbamoyl-3-{[4- (2-methoxy-2- oxoethyl)phenyl]amino}-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 497, Found 497 12-3

tert-butyl 4-{4-carbamoyl-3- [(3,5-difluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 461, Found 461 12-4

tert-butyl 4-(4-carbamoyl-3-{[6- (morpholin-4-yl) aphthal-3- yl]amino}-1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 511, Found 511 12-5

tert-butyl 4-{4-carbamoyl-3-[(6- fluoropyridin-3-yl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 444, Found 444 12-6

tert-butyl 4-[4-carbamoyl-3- (pyridazin-4-ylamino)-1H- pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 427, Found 427 12-7

tert-butyl 4-{4-carbamoyl-3-[(1- oxo-2,3-dihydro-1H-isoindol-5- yl)amino]-1H-pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 480, Found 480

tert-Butyl 4-(4-carbamoyl-3-(pyrimidin-4-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

K₃PO₄ (75 mg, 0.35 mmol), X-Phos (21 mg, 0.043 mmol), 4-bromopyrimidine (34 mg, 0.22 mmol) and tert-butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (Intermediate 35-1) (50 mg, 0.14 mmol) were suspended in t-BuOH (3 mL) and degassed with argon for 5 minutes in a microwave vial. The catalyst, Pd₂(dba)₃ (20 mg, 0.022 mmol), was added and then the mixture was heated at 80° C. for 2 hours. The mixture was then cooled to ambient temperature, Si-DMT (0.10 g) was added and the resulting mixture was allowed to stir for 1 hour. The mixture was filtered and passed through a C18 silica plug. The column was washed with acetonitrile (4 mL) and then the column eluent was evaporated to dryness in vacuo. The crude material was purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, passed through a 6 mL Silicycle Carbonate cartridge, and lyophilized to afford the title compound, Example #13-1, as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 10.40 (s, 1H), 8.83 (br s, 1H), 8.58 (s, 1H), 8.55 (d, J=7.2 Hz, 1H), 8.02 (d, J=7.2 Hz, 1H), 7.78 (br s, 1H), 7.47 (br s, 1H), 3.61-3.75 (m, 2H), 3.25 (br s, 2H), 2.90-3.15 (m, 2H), 2.30-2.54 (m, 2H), 1.94-2.04 (m, 2H), 1.38 (s, 9H).

LRMS (ESI) calc'd for C₂₀H₂₆N₈O₃ [M+H]⁺: 427. Found: 427.

The following compounds, shown in TABLE 19 were prepared according to Scheme #24 following similar procedures described for Example #13-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 19 Exact Mass Example Structure Compound Name [M + H]⁺ 13-2 

tert-butyl 4-(4-carbamoyl-3-(6- methylpyridin-2-ylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 440, Found 440 13-3 

tert-butyl 4-(4-carbamoyl-3- (pyridin-2-ylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 426, Found 426 13-4 

tert-butyl 4-(4-carbamoyl-3-(5- fluoropyridin-2-ylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 444, Found 444 13-5 

tert-butyl 4-(4-carbamoyl-3-(4- fluoropyridin-2-ylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 444, Found 444 13-6 

tert-butyl 4-(4-carbamoyl-3- (pyridazin-3-ylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 427, Found 427 13-7 

tert-butyl 4-(4-carbamoyl-3- (pyrazine-2-ylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 427, Found 427 13-8 

tert-butyl 4-(4-carbamoyl-3-(6- methylpyrazine-2-ylamino)- 1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 441, Found 441 13-9 

tert-butyl 4-(4-carbamoyl-3-(6- methoxypyridin-2-ylamino)- 1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 456, Found 456 13-10

tert-butyl 4-(4-carbamoyl-3- (2,6-dimethylpyrimidin-4- ylamino)-1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 455, Found 455 13-11

tert-butyl 4-(4-carbamoyl-3-(6- methylpyrimidin-4-ylamino)- 1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 441, Found 441 13-12

tert-butyl 4-(4-carbamoyl-3- ((5-fluoropyridin-3-yl)amino)- 1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 444, Found 444

tert-Butyl 4-(4-carbamoyl-3-{[4-(3,5-dimethylisoxazol-4-yl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

tert-Butyl 4-{3-[(4-bromophenyl)amino]-4-carbamoyl-1H pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate (Example #2-2) (50 mg, 0.10 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (22 mg, 0.10 mmol), potassium carbonate (55 mg, 0.40 mmol), and tetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) was suspended in 2:1 THF:water (1.2 mL) and heated to 100° C. for 16 hours. The mixture was then cooled to ambient temperature, diluted with MeOH, and filtered through a 0.45 micron nylon syringe filter. The filtrate was concentrated in vacuo and the residue was purified by reverse-phase preparative HPLC (using a gradient elution of 35-70% MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and lyophilized to afford the title compound, Example #14.

¹H NMR (600 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.48 (s, 1H), 7.62-7.44 (m, 3H), 7.36-7.30 (m, 1H), (7.21 (d, J=8.5 Hz, 1H), 7.16 (br s, 1H), 3.72-3.62 (m, 2H), 3.17 (s, 2H), 2.98 (br s, 2H), 2.38-2.30 (m, 5H), 2.17 (s, 3H), 2.00-1.90 (m, 2H), 1.36 (s, 9H).

LRMS (ESI) calc'd for C₂₇H₃₃N₇O₄ [M+H]⁺: 520. Found: 520.

tert-Butyl 4-{4-carbamoyl-3-[(4′-chlorobiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate

tert-Butyl 4-{3-[(3-bromophenyl)amino]-4-carbamoyl-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate (Example 12-1) (20 mg, 0.040 mmol) was combined with 4-chlorophenylboronic acid (12 mg, 0.080 mmol), SiliaCat® DPP-Pd (28 mg, 0.0080 mmol) and potassium carbonate (16 mg, 0.12 mmol) and then diluted with THF (0.8 mL). The reaction mixture was heated to 65° C. for 16 hours. After cooling to ambient temperature the mixture was filtered through celite and the filtrate was diluted with 1.0 mL DMSO. This mixture was purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier) to afford the title compound, Example #15-1.

¹H NMR (600 MHz, DMSO-d₆): δ 9.13 (s, 1H), 8.48 (s, 1H), 7.85 (s, 1H), 7.67 (d, J=8.6, 2H), 7.55 (s, 1H), 7.53-7.42 (m, 3H), 7.31 (t, J=7.9, 1H), 7.17 (s, 1H), 7.11 (d, J=7.7, 1H), 3.69 (d, J=13.7, 2H), 3.16 (s, 2H), 2.49-2.44 (m, 2H), 2.40-2.32 (m, 2H), 2.00-1.90 (m, 2H), 1.36 (s, 9H). LRMS (ESI) calc'd for C₂₈H₃₂ClN₆O₃ [M+H]⁺: 535. Found: 535.

The following compounds shown in TABLE 20 were prepared according to Scheme #25 following similar procedures described for Example #15-1, which can be achieved by those of ordinary skill in the art of organic synthesis utilizing but not limited Example 12-1 as an intermediate.

TABLE 20 Exact Mass Example Structure Compound Name [M + H]⁺ 15-2 

tert-butyl 4-{4-carbamoyl- 3-[(4′-fluorobiphenyl-3- yl)amino]-1H-pyrazol-1- yl}-4- (cyanomethyl)piperidine- 1-carboxylate Calc'd 519, Found 519 15-3 

tert-butyl 4-[3-(biphenyl- 3-ylamino)-4-carbamoyl- 1H-pyrazol-1-yl]-4- (cyanomethyl)piperidine- 1-carboxylate Calc'd 501, Found 501 15-4 

tert-butyl 4-{4-carbamoyl- 3-[(4′-methoxybiphenyl-3- yl)amino]-1H-pyrazol-1- yl}-4- (cyanomethyl)piperidine- 1-carboxylate Calc'd 531, Found 531 15-5 

tert-butyl 4-{4-carbamoyl- 3-[(4′-hydroxybiphenyl-3- yl)amino]-1H-pyrazol-1- yl}-4- (cyanomethyl)piperidine- 1-carboxylate Calc'd 517, Found 517 15-6 

tert-butyl 4-{4-carbamoyl- 3-[(4′-methylbiphenyl-3- yl)amino]-1H-pyrazol-1- yl}-4- (cyanomethyl)piperidine- 1-carboxylate Calc'd 515, Found 515 15-7 

tert-butyl 4-{4-carbamoyl- 3-[(2′-methylbiphenyl-3- yl)amino]-1H-pyrazol-1- yl}-4- (cyanomethyl)piperidine- 1-carboxylate Calc'd 515, Found 515 15-8 

tert-butyl 4-{4-carbamoyl- 3-[(3′-chlorobiphenyl-3- yl)amino]-1H-pyrazol-1- yl}-4- (cyanomethyl)piperidine- 1-carboxylate Calc'd 535, Found 535 15-9 

tert-butyl 4-{4-carbamoyl- 3-[(3-naphthalen-2- ylphenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine- 1-carboxylate Calc'd 551, Found 551 15-10

tert-butyl 4-{4-carbamoyl- 3-[(2′-fluorobiphenyl-3- yl)amino]-1H-pyrazol-1- yl}-4- (cyanomethyl)piperidine- 1-carboxylate Calc'd 519, Found 519 15-11

tert-butyl 4-{4-carbamoyl- 3-[(2′-hydroxybiphenyl-3- yl)amino]-1H-pyrazol-1- yl}-4- (cyanomethyl)piperidine- 1-carboxylate Calc'd 517, Found 517

4-[4-Carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate

To a suspension of tert-butyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate (2.0 g, 4.7 mmol) in DCM (20 mL) was added TFA (5.0 mL) dropwise. The resultant clear solution was maintained at ambient temperature for 1.5 hours. The mixture was then concentrated in vacuo, and the residue was dissolved in a mixture of MeCN/water (35 mL:15 mL) and lyophilized to afford the title compound, Example #38-1.

LRMS (ESI) acid for C₁₇H₂₀N₆O [M+H]⁺: 325. Found: 325.

The following compounds shown in TABLE 21 were prepared according to Scheme #28 and #31 following similar procedures described for Intermediate #38-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 21 Exact Mass Intermediate Structure Compound Name [M + H]⁺ 38-2

3-[4-carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidinium trifluoroacetate Calc'd 297, Found 297 38-3

3-(4-carbamoyl-3-{[4- (methylsulfonyl)phenyl]amino}- 1H-pyrazol-1-yl)-3- (cyanomethyl)azetidinium trifluoroacetate Calc'd 375, Found 375 38-4

4-{4-carbamoyl-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidinium trifluoroacetate Calc'd 344, Found 344 38-5

4-{4-carbamoyl-3-[(4- fluorophenyl)amino]-1H-pyrazol- 1-yl}-4- (cyanomethyl)piperidinium trifluoroacetate Calc'd 343, Found 343 38-6

4-(4-carbamoyl-3-{[4- (methylsulfonyl)phenyl]amino}- 1H-pyrazol-1-yl)-4- (cyanomethyl)piperidinium trifluoroacetate Calc'd 403, Found 403 38-7

4-[4-carbamoyl-3-({4- [(trifluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazol-1-yl]-4- (cyanomethyl)piperidinium trifluoroacetate Calc'd 457, Found 457 38-8

1-[(3S,4S and 3R,4R)-4-{4- carbamoyl-3-[(4- fluorophenyl)amino]-1H-pyrazol- 1-yl}-4-(cyanomethyl)-3- fluoropiperidinium trifluoroacetate Calc'd 361, Found 361

4-{4-Carbamoyl-3-[(5-fluoropyridin-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium chloride

tert-Butyl 4-(4-carbamoyl-3-(5-fluoropyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (Example 13-14) (305 mg, 0.688 mmol) was dissolved in 4 M HCl in 1,4-dioxane (7 mL). The resulting solution was maintained at ambient temperature for 2 hours. The mixture was then concentrated in vacuo to afford the title compound, Intermediate #39.

LRMS (ESI) calc'd for C₁₆H₁₈FN₇O [M+H]⁺: 344. Found: 344.

[4-({1-[1-(tert-Butoxycarbonyl)-4-(cyanomethyl)piperidin-4-yl]-4-carbamoyl-1H-pyrazol-3-yl}amino)phenyl]acetic acid

To a solution of tert-butyl 4-(4-carbamoyl-3-{[4-(2-methoxy-2-oxoethyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (Example 12-2) (0.10 g, 0.20 mmol) in THF (1.0 mL) was added a solution of LiOH (19 mg, 0.81 mmol) in water (0.8 mL). The mixture was stirred at ambient temperature for 2 hours. The mixture was then neutralized with 1N aqueous HCl to pH 3-4, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous MgSO₄, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/EtOAc) to afford the title compound, Example #18.

¹H NMR (600 MHz, DMSO-d₆): δ 11.3 (br s, 1H), 9.70 (s, 1H), 9.01 (s, 1H), 8.09 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.72 (br s, 1H), 7.09 (br s, 1H), 4.38-4.43 (m, 2H), 4.08 (s, 2H), 3.71 (s, 2H), 3.65 (br s, 2H), 3.10-3.16 (m, 2H), 2.59-2.65 (m, 2H), 1.97 (s, 9H).

LRMS (ESI) calc'd for C₂₄H₃₁N₆O₅ [M+H]⁺: 483. Found: 483.

1-[3-(Cyanomethyl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide

To a suspension of 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidinium trifluoroacetate (Intermediate #38-2) (23 mg, 0.078 mmol) in dioxane (2 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (36 mg, 0.15 mmol), followed by K₂CO₃ (23 mg, 0.078 mmol). The resulting mixture was heated to 110° C. and allowed to stir for 2 hours. The reaction was then cooled to ambient temperature, water was added and the reaction mixture was extracted with EtOAc (3×). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-100%, EtOAc/hexanes) to afford the title compound, Example #19. ¹H NMR (600 MHz, CDCl₃): δ 8.78 (s, 1H), 7.75 (s, 1H), 7.48 (d, J=7.7 Hz, 2H), 7.26 (t, J=7.9 Hz, 2H), 6.90 (t, J=7.3 Hz, 1H), 5.62 (s, 2H), 3.81 (d, J=8.6 Hz, 2H), 3.74 (d, J=8.6 Hz, 2H), 3.34 (s, 2H), 3.09 (q, J=9.1 Hz, 2H). LRMS (ESI) calc'd for C₁₇H₁₇F₃N₆O [M+H]⁺: 379. Found: 379.

1-[3-(Cyanomethyl)-1-methylazetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide

To a suspension of 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidinium trifluoroacetate (Intermediate #38-2) (50 mg, 0.17 mmol) in DCE (2.0 mL) was added sodium triacetoxyborohydride (79 mg, 0.37 mmol), followed by formaldehyde (0.050 mL, 0.67 mmol, 37 wt % in water). The resulting mixture was allowed to stir for 1 hour before saturated aqueous NaHCO₃ solution was added and the resulting mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-100%, EtOAc/hexanes) to afford the title compound, Example #20.

¹H NMR (600 MHz, CDCl₃): δ 8.76 (s, 1H), 7.81 (s, 1H), 7.49 (d, J=7.9 Hz, 2H), 7.28-7.24 (m, 2H), 6.89 (t, J=7.3 Hz, 1H), 5.74 (s, 2H), 3.66 (d, J=8.6 Hz, 2H), 3.53 (d, J=8.6 Hz, 2H), 3.32 (s, 2H), 2.39 (d, J=27.6 Hz, 3H). LRMS (ESI) calc'd for C₁₆H₁₈N₆O [M+H]⁺: 311. Found: 311.

1-[1-(Biphenyl-4-ylmethyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide

Biphenyl-4-carbaldehyde (12 mg, 0.070 mmol) was treated with a solution of 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-2) (20 mg, 0.050 mmol) and TFA (0.020 mL, 0.23 mmol) in DMF (0.65 mL). The resulting solution was then treated with MP-(OAc)₃BH (80 mg, 0.16 mmol). The resulting mixture was shaken at ambient temperature for 16 hours on an orbital shaker. The mixture was then filtered through a 0.45 micron fit and the fit was washed with DMSO (1.0 mL). The filtrate was then purified directly by reverse-phase preparative HPLC (using a gradient elution of 5-95% MeCN/water, with 0.1% v/v NH₄OH modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #21-1.

LRMS (ESI) calc'd for C₃₀H₃₁N₆O [M+H]⁺: 491. Found: 491.

The following compounds shown in TABLE 22 were prepared according to Scheme #28 following similar procedures described for Example #21-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 22 Exact Mass Example Structure Compound Name [M + H]⁺ 21-2 

1-[4-(cyanomethyl)-1- (pyridin-3- ylmethyl)piperidin-4-yl]-3- (phenylamino)-1H- pyrazole-4-carboxamide Calc'd 416, Found 416 21-3 

1-[1-(3-cyanobenzyl)-4- (cyanomethyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 440, Found 440 21-4 

1-[1-(4-cyanobenzyl)-4- (cyanomethyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 440, Found 440 21-5 

1-[4-(cyanomethyl)-1-(3- cyanopropyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 392, Found 392 21-6 

1-[1-(2-chlorobenzyl)-4- (cyanomethyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 449, Found 449 21-7 

1-[4-(cyanomethyl)-1-(4- methylbenzyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 429, Found 429 21-8 

1-[4-(cyanomethyl)-1- (naphthalene-1- ylmethyl)piperidin-4-yl]-3- (phenylamino)-1H- pyrazole-4-carboxamide Calc'd 465, Found 465 21-9 

1-[4-(cyanomethyl)-1- (cyclohexylmethyl)piperidin- 4-yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 421, Found 421 21-10

1-[1-(1,3-benzodioxol-5- ylmethyl)-4- (cyanomethyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 459, Found 459 21-11

1-[4-(cyanomethyl)-1-(3- hydroxybenzyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 431, Found 431 21-12

1-{1-[4- (acetylamino)benzyl]-4- (cyanomethyl)piperidin-4- yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 472, Found 472 21-13

1-{4-(cyanomethyl)-1-[(6- methoxynaphthalen-2- yl)methyl]piperidin-4-yl}-3- (phenylamino)-1H- pyrazole-4-carboxamide Calc'd 495, Found 495 21-14

1-[4-(cyanomethyl)-1-(2,6- dichlorobenzyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 483, Found 483 21-15

1-{4-(cyanomethyl)-1-[3- (methylsulfanyl)propyl] piperidin-4-yl}-3- (phenylamino)-1H- pyrazole-4-carboxamide Calc'd 413, Found 413 21-16

1-[4-(cyanomethyl)-1-(2- ethoxybenzyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 459, Found 459 21-17

1-{4-(cyanomethyl)-1- [(2E)-3-phenylprop-2-en-1- yl]piperidin-4-yl}-3- (phenylamino)-1H- pyrazole-4-carboxamide Calc'd 441, Found 441 21-18

1-[4-(cyanomethyl)-1-(3- fluorobenzyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 433, Found 433 21-19

1-{4-(cyanomethyl)-1-[4- (trifluoromethyl)benzyl] piperidin-4-yl}-3- (phenylamino)-1H- pyrazole-4-carboxamide Calc'd 483, Found 483 21-20

1-[1-(1-benzofuran-2- ylmethyl)-4- (cyanomethyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 455, Found 455 21-21

1-[1-(4-chloro-2- fluorobenzyl)-4- (cyanomethyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 467, Found 467 21-22

1-[4-(cyanomethyl)-1-(4- propylbenzyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 457, Found 457 21-23

1-[4-(cyanomethyl)-1-(2,6- difluorobenzyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 451, Found 451 21-24

1-{4-(cyanomethyl)-1-[4-(1- methylethyl)benzyl]piperidin- 4-yl}-3-(phenylamino)- 1H-pyrazole-4-carboxamide Calc'd 457, Found 457 21-25

1-[4-(cyanomethyl)-1-(3- phenylprop-2-yn-1- yl)piperidin-4-yl]-3- (phenylamino)-1H- pyrazole-4-carboxamide Calc'd 439, Found 439 21-26

1-[4-(cyanomethyl)-1- (2,3,6- trifluorobenzyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 469, Found 469 21-27

1-{4-(cyanomethyl)-1-[4-(1- methylethoxy)benzyl]piperidin- 4-yl}-3-(phenylamino)- 1H-pyrazole-4-carboxamide Calc'd 473, Found 473 21-28

1-[4-(cyanomethyl)-1-(3,4- dimethylbenzyl)piperidin-4- yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 443, Found 443 21-29

methyl 2-({4-[4-carbamoyl- 3-(phenylamino)-1H- pyrazol-1-yl]-4- (cyanomethyl)piperidin-1- yl}methyl)benzoate Calc'd 473, Found 473

1-(4-(Cyanomethyl)-1-((1-ethyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide

To a reaction vial was added 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-4) (0.020 g, 0.058 mmol), 1-ethyl-1H-imidazole-2-carbaldehyde (0.0072 g, 0.058 mmol), Na(OAc)₃BH (0.062 g, 0.29 mmol), TFA (0.030 g, 0.26 mmol) suspended in DMF (0.97 mL). The reaction vessel was sealed and heated to 50° C. with stirring for 12 hours. The completed reaction was directly purified by reverse phase preparative HPLC (using a gradient elution of 0-95% ACN/water with 0.1% v/v NH₄OH modifier) to afford the title compound, Example #22-1.

LRMS (ESI) calc'd for C₂₂H₂₆FN₉O [M+H]⁺: 452. Found: 452.

The following compounds shown in TABLE 23 were prepared according to Scheme #37 following similar procedures described for Example #22-1, which can be achieved by those of ordinary skill in the art of organic synthesis utilizing but not limited to Intermediates #38-4 and 38-5 as intermediates.

TABLE 23 Exact Mass Example Structure Compound Name [M + H]⁺ 22-2 

1-[4-(cyanomethyl)-1-(pyridin- 3-ylmethyl)piperidin-4-yl]-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 435, found 435 22-3 

1-[4-(cyanomethyl)-1- (cyclohexylmethyl)piperidin-4- yl]-3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 440, found 440 22-4 

1-{4-(cyanomethyl)-1-[(4- methyl-1H-imidazol-2- yl)methyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 438, found 438 22-5 

1-[4-(cyanomethyl)-1-(1H- pyrazol-4-ylmethyl)piperidin- 4-yl]-3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 424, found 424 22-6 

1-[4-(cyanomethyl)-1- (cyclohexylmethyl)piperidin-4- yl]-3-[(4-fluorophenyl)amino]- 1H-pyrazole-4-carboxamide Calc'd 439, found 439 22-7 

1-[1-benzyl-4- (cyanomethyl)piperidin-4-yl]- 3-[(4-fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 433, found 433 22-8 

1-[1-benzyl-4- (cyanomethyl)piperidin-4-yl]- 3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 434, found 434 22-9 

1-[4-(cyanomethyl)-1-(2- fluorobenzyl)piperidin-4-yl]-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 452, found 452 22-10

1-[4-(cyanomethyl)-1-(3- fluorobenzyl)piperidin-4-yl]-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 452, found 452 22-11

1-[4-(cyanomethyl)-1-(4- fluorobenzyl)piperidin-4-yl]-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 452, found 452 22-12

1-[4-(cyanomethyl)-1- (imidazo[1,2-a]pyridin-2- ylmethyl)piperidin-4-yl]-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 474, found 474 22-13

1-[4-(cyanomethyl)-1-(1H- pyrazol-5-ylmethyl)piperidin- 4-yl]-3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 424, found 424 22-14

1-[4-(cyanomethyl)-1-(pyrazin- 2-ylmethyl)piperidin-4-yl]-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 436, found 436 22-15

1-{4-(cyanomethyl)-1-[(2- methyl-1,3-thiazol-5- yl)methyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 455, found 455 22-16

1-{4-(cyanomethyl)-1-[(2,2- dimethyltetrahydro-2H-pyran- 4-yl)methyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 470, found 470 22-17

1-[4-(cyanomethyl)-1- (pyrazolo[1,5-a]pyridin-3- ylmethyl)piperidin-4-yl]-3-[(2- fluoropyridin-4-yl)amino-1H- pyrazole-4-carboxamide Calc'd 474, found 474 22-18

1-[4-(cyanomethyl)-1-(1H- pyrrolo[2,3-b]pyridin-4- ylmethyl)piperidin-4-yl]-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 474, found 474 22-19

1-[4-(cyanomethyl)-1-(furan-2- ylmethyl)piperidin-4-yl]-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 424, found 424 22-20

1-[4-(cyanomethyl)-1-(1H- indol-5-ylmethyl)piperidin-4- yl]-3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 473, found 473 22-21

1-[4-(cyanomethyl)-1-(1H- indol-7-ylmethyl)piperidin-4- yl]-3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 473, found 473 22-22

1-{4-(cyanomethyl)-1-[(2- fluoro-5-methylpyridin-3- yl)methyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 467, found 467 22-23

1-{4-(cyanomethyl)-1-[(2- fluoropyridin-3- yl)methyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 453, found 453 22-24

1-[4-(cyanomethyl)-1-{[3-(1- hydroxy-1- methylethyl)cyclobutyl]methyl} piperidin-4-yl]-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 470, found 470 22-25

1-[4-(cyanomethyl)-1-(1,3- thiazol-4-ylmethyl)piperidin-4- yl]-3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 441, found 441 22-26

1-[4-(cyanomethyl)-1-(1,3- oxazol-4-ylmethyl)piperidin-4- yl]-3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 425, found 425 22-27

1-{4-(cyanomethyl)-1-[(5- methylisoxazol-3- yl)methyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 439, found 439 22-28

1-[4-(cyanomethyl)-1-(1,3- oxazol-2-ylmethyl)piperidin-4- yl]-3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 425, found 425 22-29

1-{4-(cyanomethyl)-1-[(1- methyl-1H-pyrazol-5- yl)methyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 438, found 438 22-30

1-{4-(cyanomethyl)-1-[(1- methyl-1H-pyrazol-3- yl)methyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 438, found 438 22-31

1-[4-(cyanomethyl)-1- (isoxazol-3- ylmethyl)piperidin-4-yl]-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 425, found 425 22-32

1-{4-(cyanomethyl)-1-[(6- fluoropyridin-2- yl)methyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 453, found 453 22-33

1-[4-(cyanomethyl)-1- (pyrazolo[1,5-a]pyridin-7- ylmethyl)piperidin-4-yl]-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 474, found 474 22-34

1-[4-(cyanomethyl)-1- (pyrazolo[1,5-a]pyridin-2- ylmethyl)piperidin-4-yl]-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 474, found 474 22-35

1-[4-(cyanomethyl)-1- (pyridazin-3- ylmethyl)piperidin-4-yl]-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 436, found 436 22-36

1-{4-(cyanomethyl)-1-[(5- fluoropyridin-2- yl)methyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 453, found 453 22-37

1-{4-(cyanomethyl)-1-[(3- methoxycyclobutyl)methyl] piperidin-4-yl}-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 442, found 442 22-38

1-{4-(cyanomethyl)-1-[(5- fluoropyridin-3- yl)methyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 453, found 453 22-39

1-[4-(cyanomethyl)-1-(1H- indol-2-ylmethyl)piperidin-4- yl]-3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 473, found 473 22-40

1-{4-(cyanomethyl)-1-[(1,5- dimethyl-1H-pyrazol-4- yl)methyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 452, found 452 22-41

1-[1-(1H-benzimidazol-2- ylmethyl)-4- (cyanomethyl)piperidin-4-yl]- 3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 474, found 474 22-42

1-{4-(cyanomethyl)-1-[(3- methyl-4,5-dihydroisoxazol-5- yl)methyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 441, found 441 22-43

1-[4-(cyanomethyl)-1-(1H- indol-2-ylmethyl)piperidin-4- yl]-3-[(4-fluorophenyl)amino]- 1H-pyrazole-4-carboxamide Calc'd 472, found 472 22-44

1-{4-(cyanomethyl)-1-[(2- fluoro-5-methylpyridin-3- yl)methyl]piperidin-4-yl}-3- [(4-fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 466, found 466 22-45

1-[4-(cyanomethyl)-1- (isoxazol-3- ylmethyl)piperidin-4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 424, found 424 22-46

1-{4-(cyanomethyl)-1-[(6- fluoropyridin-2- yl)methyl]piperidin-4-yl}-3- [(4-fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 452, found 452 22-47

1-[4-(cyanomethyl)-1- (pyridazin-3- ylmethyl)piperidin-4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 435, found 435 22-48

1-{4-(cyanomethyl)-1-[(5- fluoropyridin-2- yl)methyl]piperidin-4-yl}-3- [(4-fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 452, found 452 22-49

1-{4-(cyanomethyl)-1-[(5- fluoropyridin-3- yl)methyl]piperidin-4-yl}-3- [(4-fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 452, found 452 22-50

1-{4-(cyanomethyl)-1-[(4- fluoropyridin-2- yl)methyl]piperidin-4-yl}-3- [(4-fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 452, found 452 22-51

1-[4-(cyanomethyl)-1-(pyridin- 3-ylmethyl)piperidin-4-yl]-3- [(4-fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 434, found 434 22-52

1-[4-(cyanomethyl)-1-(pyrazin- 2-ylmethyl)piperidin-4-yl]-3- [(4-fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 435, found 435 22-53

1-[4-(cyanomethyl)-1-(1H- pyrrolo[2,3-b]pyridin-4- ylmethyl)piperidin-4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 473, found 473 22-54

1-[4-(cyanomethyl)-1-(furan-2- ylmethyl)piperidin-4-yl]-3-[(4- fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 423, found 423 22-55

1-[4-(cyanomethyl)-1-(1H- indol-5-ylmethyl)piperidin-4- yl]-3-[(4-fluorophenyl)amino]- 1H-pyrazole-4-carboxamide Calc'd 472, found 472 22-56

1-[4-(cyanomethyl)-1-(1H- indol-6-ylmethyl)piperidin-4- yl]-3-[(4-fluorophenyl)amino]- 1H-pyrazole-4-carboxamide Calc'd 472, found 472 22-57

1-[4-(cyanomethyl)-1-(1H- indol-4-ylmethyl)piperidin-4- yl]-3-[(4-fluorophenyl)amino]- 1H-pyrazole-4-carboxamide Calc'd 472, found 472 22-58

1-[4-(cyanomethyl)-1-(1H- indol-7-ylmethyl)piperidin-4- yl]-3-[(4-fluorophenyl)amino]- 1H-pyrazole-4-carboxamide Calc'd 472, found 472 22-59

1-[1-(2-chlorobenzyl)-4- (cyanomethyl)piperidin-4-yl]- 3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 468, found 468 22-60

1-[4-(cyanomethyl)-1-(4- hydroxybenzyl)piperidin-4-yl]- 3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 450, found 450 22-61

1-[1-(3-chlorobenzyl)-4- (cyanomethyl)piperidin-4-yl]- 3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 468, found 468 22-62

1-[1-(3-cyanobenzyl)-4- (cyanomethyl)piperidin-4-yl]- 3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 459, found 459 22-63

1-[4-(cyanomethyl)-1-(3- methoxybenzyl)piperidin-4- yl]-3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 464, found 464 22-64

1-[4-(cyanomethyl)-1-(2- phenylethyl)piperidin-4-yl]-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 448, found 448 22-65

1-[4-(cyanomethyl)-1-(4- methoxybenzyl)piperidin-4- yl]-3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 464, found 464 22-66

1-[4-(cyanomethyl)-1-(2- methoxybenzyl)piperidin-4- yl]-3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 464, found 464 22-67

1-{4-(cyanomethyl)-1-[(6-oxo- 1,6-dihydropyridin-2- yl)methyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 451, found 451 22-68

1-{4-(cyanomethyl)-1-[(6- hydroxypyridin-3- yl)methyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 451, found 451 22-69

1-[1-(4-cyanobenzyl)-4- (cyanomethyl)piperidin-4-yl]- 3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 459, found 459 22-70

1-[4-(cyanomethyl)-1-(3- hydroxybenzyl)piperidin-4-yl]- 3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 450, found 450 22-71

1-[1-(4-chlorobenzyl)-4- (cyanomethyl)piperidin-4-yl]- 3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 468, found 468 22-72

1-[1-(2-cyanobenzyl)-4- (cyanomethyl)piperidin-4-yl]- 3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 459, found 459

1-(4-(Cyanomethyl)-1-(1-phenylethyl)piperidin-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide

To a solution of 1-(4-(cyanomethyl)piperidin-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide (Intermediate #38-5) (50 mg, 0.11 mmol) in MeOH (0.32 mL) and DMF (0.063 mL) was added acetophenone (41 mg, 0.34 mmol) and acetic acid (0.065 mL, 1.1 mmol). The reaction mixture was allowed to stir at room temperature for 15 minutes. Sodium cyanoborohydride (7 mg, 0.1 mmol) was added and the reaction mixture was allowed to stir for 24 hours at ambient temperature. The mixture was then purified directly by mass-triggered reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo. The residue was dissolved in MeOH and passed through a Si-Carbonate cartridge to afford the title compound as a free base.

¹H NMR (500 MHz, DMSO-d₆): δ 9.57 (br s, 1H), 9.02 (s, 1H), 8.46 (s, 1H), 7.52-7.49 (m, 4H), 7.43 (s, 4H), 7.23 (br s, 1H), 7.04 (t, J=8.5 Hz, 2H), 4.47 (m, 1H), 3.91-3.88 (m, 1H), 3.12 (s, 2H), 3.02-3.00 (m, 1H), 2.86-2.80 (m, 2H), 2.68-2.66 (m, 2H), 2.31-2.26 (m, 1H), 2.16-2.12 (m, 1H), 1.59 (m, d, J=7 Hz, 2H).

LRMS (ESI) calc'd for C₂₅H₂₇FN₆O [M+H]⁺: 447. Found: 447.

1-(4-(Cyanomethyl)-1-(2-fluoroethyl)piperidin-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide

To a sealed vial was added 2-fluoroethanol (0.0090 g, 0.14 mmol), PS-IBX (0.28 g, 0.28 mmol, 1.0 mmol/g) suspended in DCE (1.0 mL). The vial was capped and shaken at RT for 16 hours. The reaction was passed though a syringe filter and the eluent was collected into a reaction vial. To the reaction vial was added 4-(4-carbamoyl-3-((4-fluorophenyl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidin-1-ium 2,2,2-trifluoroacetate (Intermediate #38-5) (0.020 g, 0.058 mmol), TFA (0.020 mL, 0.26 mmol), Na(OAc)₃BH (0.037 g, 0.18 mmol) suspended in DMF (0.50 mL). The reaction vial was capped and heated to 50° C. for 4 hours. The completed reaction was concentrated in vacuo and the residue taken up in DMF (1.0 mL). The crude reaction was passed through a syringe filter and the eluent was directly purified by reverse phase preparative HPLC (using a gradient elution of 0-95% ACN/water with 0.1% v/v TFA modifier). The collected HPLC fraction was concentrated in vacuo and the residue was taken up in MeOH and passed through a Si-Carbonate SPE cartridge. The eluent was collected and evaporated to afford the title compound.

LRMS (ESI) calc'd for C₁₉H₂₂F₂N₆O [M+H]⁺: 389. Found: 389.

The following compounds shown in TABLE 24 were prepared according to Scheme #38 following similar procedures described for Example #24-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 24 Exact Mass Example Structure Compound Name [M + H]⁺ 24-2

1-[4-(cyanomethyl)-1- (cyclopropylmethyl) piperidin-4-yl]-3-[(4- fluorophenyl)amino]- 1H-pyrazole-4- carboxamide Calc'd 397, found 397

1-(4-(Cyanomethyl)-1-(pyridin-2-yl)piperidin-4-yl)-3-(4-fluorophenylamino)-1H-pyrazole-4-carboxamide

A mixture of 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-5) (52 mg, 0.11 mmol), copper (I) iodide (2 mg, 0.01 mmol), L-proline (3 mg, 0.02 mmol) and K₃PO₄ (48 mg, 0.23 mmol) was dissolved in DMSO (0.16 mL). 2-Bromopyridine (0.011 mL, 0.11 mmol) was added, and the resulting mixture was heated to 90° C. and allowed to stir for 72 hours. The reaction mixture was then allowed to cool to ambient temperature and was filtered. The filtrate was purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound as a solid.

¹H NMR (600 MHz, DMSO-d₆): δ 9.02 (br s, 1H), 8.51 (s, 1H), 8.06 (dd, J=5.3, 1.4 Hz, 1H), 7.78 (br s, 1H), 7.60-7.45 (m, 3H), 7.25-7.10 (m, 2H), 7.10-7.00 (m, 2H), 6.85-6.75 (m, 1H), 4.00-3.92 (m, 2H), 3.32-3.20 (m, 2H), 3.18 (s, 2H), 2.51-2.44 (m, 2H), 2.11 (ddd, J=14.1, 10.1, 4.0 Hz, 2H).

LRMS (ESI) calc'd for C₂₂H₂₂FN₇O [M+H]⁺: 420. Found: 420.

1-[4-(Cyanomethyl)-1-pyrimidin-4-ylpiperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide

To a solution of 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-5) (50 mg, 0.11 mmol) in DCE (1.0 mL) was added DIPEA (0.096 mL, 0.55 mmol) followed by 4-bromopyrimidine (32 mg, 0.16 mmol). The reaction mixture was heated under microwave irradiation to 130° C. and allowed to stir for 15 minutes. The reaction mixture was then cooled to ambient temperature and diluted with a mixture of DCM and IPA. The resulting mixture was sequentially washed with water, brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The resulting residue was purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #26, as a solid.

LRMS (ESI) calc'd for C₂₁H₂₁FN₈O [M+H]⁺: 421. Found: 421.

Methyl 4-(4-carbamoyl-3-(4-(trifluoromethylsulfonyl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

4-[4-Carbamoyl-3-({4-[(trifluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-7) (30 mg, 0.053 mmol) was dissolved in DCM (1.0 mL). DIPEA (0.055 mL, 0.32 mmol) was added, followed by methyl chloroformate (0.024 mL, 0.32 mmol). The resulting mixture was allowed to stir at ambient temperature for 30 minutes. The solvent was removed in vacuo and the crude residue was purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #27-1, as a solid.

¹H NMR (600 MHz, DMSO-d₆): δ 9.87 (s, 1H), 8.57 (s, 1H), 7.93-7.84 (m, 4H), 7.68 (s, 1H), 7.34 (s, 1H), 3.72 (d, J=14.1 Hz, 2H), 3.57 (s, 3H), 3.22 (s, 2H), 3.12-3.02 (m, 2H), 2.37 (d, J=14.5 Hz, 2H), 2.01 (ddd, J=13.9, 9.9, 4.2 Hz, 2H).

LRMS (ESI) calc'd for C₂₀H₂₁F₃N₆O₅S [M+H]⁺: 515. Found: 515.

The following compounds shown in TABLE 25 were prepared according to Scheme #28 following similar procedures described for Example #27-1, which can be achieved by those of ordinary skill in the art of organic synthesis utilizing but not limited to Intermediates #38-1, 38-6, and 38-7.

TABLE 25 Exact Mass Example Structure Compound Name [M + H]⁺ 27-2

2-methoxyethyl 4-(4- carbamoyl-3-(4- (trifluoromethylsulfonyl) phenylamino)-1H-pyrazol-1- yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 559, Found 559 27-3

methyl 4-(4-carbamoyl-3- {[4- (methylsulfonyl)phenyl] amino}-1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 461, Found 461 27-4

benzyl 4-[4-carbamoyl-3- (phenylamino)-1H-pyrazol- 1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 459, Found 459 27-5

methyl 4-[4-carbamoyl-3- (phenylamino)-1H-pyrazol- 1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 383, Found 383

2-Methoxy-1,1-dimethylethyl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate

A solution of 1-methoxy-2-methyl-2-propanol (91 mg, 0.88 mmol) in THF (1.5 mL) and TEA (0.20 mL, 1.4 mmol) was cooled to 0° C. and allowed to stir. Triphosgene (260 mg, 0.876 mmol) was added and the resulting mixture was allowed to warm to ambient temperature and was stirred for 15 minutes. A solution of 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-5) (80 mg, 0.18 mmol) and TEA (0.061 mL, 0.44 mmol) in DCM (1.0 mL) was then added to the reaction mixture dropwise. The resulting mixture was heated to 50° C. and allowed to stir for 16 hours. The solution was cooled to ambient temperature, diluted with DCM, washed with water, dried over anhydrous MgSO₄, and concentrated in vacuo. The resulting residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound, Example #28.

¹H NMR (600 MHz, acetone-d₆): δ 9.16 (s, 1H), 8.45 (s, 1H), 7.65-7.56 (m, 2H), 7.15 (br s, 1H), 7.03-6.98 (m, 2H), 6.47 (br s, 1H), 3.85 (dt, J=13.9, 4.3 Hz, 2H), 3.49 (s, 2H), 3.30 (s, 3H), 3.16 (s, 2H), 3.15-3.02 (m, 2H), 2.62-2.54 (m, 2H), 2.11-2.04 (m, 2H), 1.39 (s, 6H).

LRMS (ESI) calc'd for C₂₃H₂₉FN₆O₄ [M+H]⁺: 473. Found: 473.

1-Hydroxy-2-methylpropan-2-yl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate

Step A: 1-Methoxy-2-methyl-1-oxopropan-2-yl4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate (Example 29-A)

To a solution of methyl 2-hydroxyisobutyrate (0.20 mL, 1.8 mmol) in THF (4 mL) was added TEA (0.49 mL, 3.5 mmol). The mixture was cooled to 0° C. and allowed to stir. Phosgene (1.70 g, 3.51 mmol, 20 w % in toluene) was added and the resulting mixture was allowed to stir at 0° C. for 3 hours. The mixture was then concentrated in vacuo. The residue was diluted with THF (5 mL) and concentrated in vacuo again. To the resulting residue was added DCM (3 mL), followed by TEA (0.49 mL, 3.5 mmol). The mixture was cooled to 0° C., and allowed to stir. 4-{4-Carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-5) (0.20 g, 0.44 mmol) was added and the resulting mixture was allowed to stir at 0° C. for 30 minutes. The reaction mixture was diluted with saturated aqueous NaHCO₃ and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 50-100% EtOAc/hexanes) to afford the title compound, Example 29-A.

¹H NMR (600 MHz, acetone-d₆): δ 9.13 (s, 1H), 8.44 (s, 1H), 7.57 (dd, J=8.4, 3.6 Hz, 2H), 7.13 (br s, 1H), 6.98 (t, J=8.4 Hz, 2H) 6.52 (br s, 1H), 3.76-3.90 (m, 2H), 3.60 (s, 3H), 3.04-3.17 (m, 4H), 2.50-2.64 (m, 2H), 2.00-2.12 (m, 2H), 1.47 (s, 6H).

LRMS (ESI) calc'd for C₂₃H₂₈FN₆O₅ [M+H]⁺: 487. Found: 487.

Step B. 1-Hydroxy-2-methylpropan-2-yl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate

To a solution of 1-methoxy-2-methyl-1-oxopropan-2-yl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate (70 mg, 0.14 mmol) in THF (1.9 mL) at ambient temperature was added LiBH₄ (25 mg, 1.2 mmol). The mixture was allowed to stir at ambient temperature for 3 hours. The mixture was then diluted with EtOAc and saturated aqueous ammonium chloride. The organic layer was separated, washed with water, brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/EtOAc) to afford the title compound, Example 29.

¹H NMR (600 MHz, acetone-d₆): δ 9.13 (s, 1H), 8.41 (s, 1H), 7.54-7.60 (m, 2H), 7.13 (br s, 1H), 6.95-6.99 (m, 2H), 6.45 (br s, 1H), 3.84-4.00 (m, 2H), 3.85 (s, 2H), 3.06-3.21 (m, 4H), 2.80 (s, 1H), 2.50-2.64 (m, 2H), 2.04-2.12 (m, 2H), 1.14 (s, 6H).

LRMS (ESI) calc'd for C₂₂H₂₈FN₆O₄ [M+H]⁺: 459. Found: 459.

2,2,2-Trifluoroethyl 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate

To a solution of 2,2,2-trifluoroethanol (15 mg, 0.15 mmol) in acetonitrile (1.0 mL) was added TEA (0.043 mL, 0.31 mmol) followed by N,N′-disuccinimidyl carbonate (59 mg, 0.23 mmol). The resulting mixture was allowed to stir at ambient temperature for 4 hours. A solution of 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-4) (70 mg, 0.15 mmol) and TEA (0.043 mL, 0.31 mmol) in DMSO (1.0 mL) was then added to the reaction mixture dropwise. The resulting mixture was heated to 50° C. and allowed to stir for 16 hours. The crude reaction mixture was cooled to ambient temperature and purified directly by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #30-1.

¹H NMR (600 MHz, acetone-d₆): δ 9.76 (s, 1H), 8.57 (s, 1H), 7.93 (d, J=5.7 Hz, 1H), 7.39 (s, 1H), 7.28-7.20 (br m, 2H), 6.66 (br s, 1H), 4.64 (q, J=8.9 Hz, 2H), 3.95 (d, J=14.0 Hz, 2H), 3.39-3.15 (m, 4H), 2.74-2.63 (m, 2H), 2.21 (ddd, J=14.6, 10.6, 4.2 Hz, 2H).

LRMS (ESI) calc'd for C₁₉H₁₉F₄N₇O₃ [M+H]⁺: 470. Found: 470.

The following compounds shown in TABLE 26 were prepared according to Scheme #28 following similar procedures described for Example #30-1, which can be achieved by those of ordinary skill in the art of organic synthesis utilizing but not limited to Intermediates #38-1, 38-2, 38-3, 38-4, 38-5, 38-7, and 38-8.

TABLE 26 Exact Mass Example Structure Compound Name [M + H]⁺ 30-2

2,2,2-trifluoroethyl 4-(4- carbamoyl-3-(4- fluorophenylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 469, Found 469 30-3

1,1,1-trifluoropropan-2-yl 4-(4- carbamoyl-3-(4- fluorophenylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 483, Found 483 30-4

cyclobutyl 4-(4-carbamoyl-3-(4- fluorophenylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 441, Found 441 30-5

cyclobutylmethyl 4-(4- carbamoyl-3-(4- fluorophenylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 455, Found 455 30-6

(2,2- difluorocyclopropyl)methyl 4- (4-carbamoyl-3-(4- fluorophenylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 477, Found 477 30-7

2,2-difluoroethyl 4-(4- carbamoyl-3-(4- fluorophenylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 451, Found 451 30-8

(1-methylcyclopropyl)methyl 4- (4-carbamoyl-3-(4- fluorophenylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 455, Found 455 30-9

1,3-difluoropropan-2-yl 4-(4- carbamoyl-3-(4- fluorophenylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 465, Found 465 30-10

(trimethylsilyl)methyl 4-(4- carbamoyl-3-(4- fluorophenylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 473, Found 473 30-11

2,2-difluoro-3-hydroxypropyl 4- (4-carbamoyl-3-(4- fluorophenylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 481, Found 481 30-12

1-cyclopropylethyl 4-(4- carbamoyl-3-(4- fluorophenylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 455, Found 455 30-13

(1-hydroxycyclopropyl)methyl 4-(4-carbamoyl-3-(4- fluorophenylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 457, Found 457 30-14

(R)-1,1,1-trifluoropropan-2-yl 4-(4-carbamoyl-3-(4- fluorophenylamino)-1H- pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 483, Found 483 30-15

2,2-difluoroethyl 4-(4- carbamoyl-3-(5-fluoropyridin- 3-ylamino)-1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 452, Found 452 30-16

tetrahydrofuran-3-yl 4-{4- carbamoyl-3-[(2-fluoropyridin- 4-yl)amino]-1H-pyrazol-1-yl}- 4-(cyanomethyl)piperidine-1- carboxylate Calc'd 458, Found 458 30-17

tetrahydro-2H-pyran-4-yl 4-{4- carbamoyl-3-[(2-fluoropyridin- 4-yl)amino]-1H-pyrazol-1-yl}- 4-(cyanomethyl)piperidine-1- carboxylate Calc'd 472, Found 472 30-18

oxetan-3-yl 4-{4-carbamoyl-3- [(4-fluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 443, Found 443 30-19

cyclopropylmethyl 4-{4- carbamoyl-3-[(4- fluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 441, Found 441 30-20

(3-methyloxetan-3-yl)methyl 4- {4-carbamoyl-3-[(4- fluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 471, Found 471 30-21

tetrahydro-2H-pyran-4-ylmethyl 4-{4-carbamoyl-3-[(4- fluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 485, Found 485 30-22

tetrahydrofuran-3-ylmethyl 4- {4-carbamoyl-3-[(4- fluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 471, Found 471 30-23

1-methoxypropan-2-yl 4-{4- carbamoyl-3-[(4- fluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 459, Found 459 30-24

2-methoxypropyl 4-{4- carbamoyl-3-[(4- fluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 459, Found 459 30-25

tetrahydro-2H-pyran-3-yl 4-{4- carbamoyl-3-[(4- fluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 471, Found 471 30-26

oxetan-3-yl 4-(4-carbamoyl-3- (4- (trifluoromethylsulfonyl)phenyl amino)-1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 557, Found 557 30-27

2,2-difluoroethyl 4-(4- carbamoyl-3-(2-fluoropyridin- 4-ylamino)-1H-pyrazol-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 452, Found 452 30-28

2-methylpropyl 4-[4-carbamoyl- 3-(phenylamino)-1H-pyrazol-1- yl]-4-(cyanomethyl)piperidine- 1-carboxylate Calc'd 425, Found 425 30-29

2,2-dimethylpropyl 4-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 439, Found 439 30-30

cyclopentyl 4-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-4-(cyanomethyl)piperidine- 1-carboxylate Calc'd 437, Found 437 30-31

cyclohexyl 4-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-4-(cyanomethyl)piperidine- 1-carboxylate Calc'd 451, Found 451 30-32

3-fluorobenzyl 4-[4-carbamoyl- 3-(phenylamino)-1H-pyrazol-1- yl]-4-(cyanomethyl)piperidine- 1-carboxylate Calc'd 477, Found 477 30-33

2-fluorobenzyl 4-[4-carbamoyl- 3-(phenylamino)-1H-pyrazol-1- yl]-4-(cyanomethyl)piperidine- 1-carboxylate Calc'd 477, Found 477 30-34

2,3-dihydro-1H-inden-2-yl 4-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 485, Found 485 30-35

2-methoxyethyl 4-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 427, Found 427 30-36

4-carbamoyl-1-[4- (cyanomethyl)-1-{[(3R and 3S)- tetrahydrofuran-3- yloxy]carbonyl}piperidin-4-yl]- 3-(phenylamino)-1H-pyrazol-2- ium Calc'd 439, Found 439 30-37

tetrahydro-2H-pyran-4-yl 4-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 453, Found 453 30-38

pyridin-3-ylmethyl 4-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 460, Found 460 30-39

pyridin-3-ylmethyl 4-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 460, Found 460 30-40

pyridin-4-ylmethyl 4-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 460, Found 460 30-41

2-morpholin-4-ylethyl 4-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 482, Found 482 30-42

1-methylpiperidin-4-yl 4-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-l-yl]-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 466, Found 466 30-43

2-(4-methylpiperazin-1-yl)ethyl 4-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-4-(cyanomethyl)piperidine- 1-carboxylate Calc'd 495, Found 495 30-44

(1-methylpiperidin-4-yl)methyl 4-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-4-(cyanomethyl)piperidine- 1-carboxylate Calc'd 480, Found 480 30-45

3,3,3-Trifluoropropyl 4-{4- carbamoyl-3-[(4- fluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 483, Found 483 30-46

tetrahydrofuran-3-yl 4-{4- carbamoyl-3-[(4- fluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 457, Found 457 30-47

tetrahydro-2H-pyran-4-yl 4-{4- carbamoyl-3-[(4- fluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 471, Found 471 30-48

2-methoxyethyl 4-{4- carbamoyl-3-[(4- fluorophenyl)amino]-1H- pyrazol-1-yl}-4- (cyanomethyl)piperidine-1- carboxylate Calc'd 445, Found 445 30-49

Cyclopropylmethyl 4-{4- carbamoyl-3-[(2-fluoropyridin- 4-yl)amino]-1H-pyrazol-1-yl}- 4-(cyanomethyl)piperidine-1- carboxylate Calc'd 442, Found 442 30-50

2-fluoroethyl 3-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-3-(cyanomethyl)azetidine-1- carboxylate Calc'd 387, Found 387 30-51

2-methylpropyl 3-[4-carbamoyl- 3-(phenylamino)-1H-pyrazol-1- yl]-3-(cyanomethyl)azetidine-1- carboxylate Calc'd 397, Found 397 30-52

cyclopentyl 3-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-3-(cyanomethyl)azetidine-1- carboxylate Calc'd 409, Found 409 30-53

benzyl 3-[4-carbamoyl-3- (phenylamino)1H-pyrazol-1- yl]-3-(cyanomethyl)azetidine-1- carboxylate Calc'd 431, Found 431 30-54

2-naphthalen-1-ylethyl 3-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 495, Found 495 30-55

2-morpholin-4-ylethyl 3-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 454, Found 454 30-56

2,2-dimethylpropyl 3-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 411, Found 411 30-57

cyclohexyl 3-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-3-(cyanomethyl)azetidine-1- carboxylate Calc'd 423, Found 423 30-58

2-phenylethyl 3-[4-carbamoyl- 3-(phenylamino)-1H-pyrazol-1- yl]-3-(cyanomethyl)azetidine-1- carboxylate Calc'd 445, Found 445 30-59

2-methoxyethyl 3-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 399, Found 399 30-60

2-ethoxy-2-oxoethyl 3-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 427, Found 427 30-61

3-methoxypropyl 3-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 413, Found 413 30-62

tetrahydrofuran-3-yl 3-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 411, Found 411 30-63

tetrahydro-2H-pyran-4-yl 3-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylase Calc'd 425, Found 425 30-64

2-(2-oxopyrrolidin-1-yl)ethyl 3- [4-carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 452, Found 452 30-65

pyridin-3-ylmethyl 3-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 432, Found 432 30-66

pyridin-4-ylmethyl 3-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 432, Found 432 30-67

2-pyridin-2-ylethyl 3-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 446, Found 446 30-68

3-pyridin-3-ylpropyl 3-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 460, Found 460 30-69

2-methoxybenzyl 3-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 461, Found 461 30-70

3-methoxybenzyl 3-[4- carbarnoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 461, Found 461 30-71

3-(dimethylamino)propyl 3-[4- carbamoyl-3-(phenylamino)- 1H-pyrazol-1-yl]-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 426, Found 426 30-72

2-(4-methylpiperazin-1-yl)ethyl 3-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-3-(cyanomethyl)azetidine-1- carboxylate Calc'd 467, Found 467 30-73

(1-methylpiperidin-4-yl)methyl- 3-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1- yl]-3-(cyanomethyl)azetidine-1- carboxylate Calc'd 452, Found 452 30-74

cyclopentyl 3-(4-carbamoyl-3- {[4- (methylsulfonyl)phenyl]amino}- 1H-pyrazol-1-yl)-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 487, Found 973 (2M + H) 30-75

tetrahydrofuran-3-yl 3-(4- carbamoyl-3-{[4- (methylsulfonyl)phenyl]amino)- 1H-pyrazol-1-yl)-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 489, Found 489 30-76

tetrahydro-2H-pyran-4-yl 3-(4- carbamoyl-3-{[4- (methylsulfonyl)phenyl]amino}- 1H-pyrazol-1-yl)-3- (cyanomethyl)azetidine-1- carboxylate Calc'd 503, Found 503 30-77

(1S)-1-cyclopropylethyl 4-{4- carbamoyl-3-[(2-fluoropyridin- 4-yl)amino]-1H-pyrazol-1-yl}- 4-(cyanomethyl)piperidine-1- carboxylate Calc'd 456, Found 456 30-78

(1R)-1-cyclopropylethyl 4-{4- carbamoyl-3-[(2-fluoropyridin- 4-yl)amino]-1H-pyrazol-1-yl}- 4-(cyanomethyl)piperidine-1- carboxylate Calc'd 456, Found 456

2-Hydroxy-1-methylethyl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate

To a solution of 1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate (Example 30-51) (86 mg, 0.15 mmol) in THF (1.0 mL) was added a solution of TBAF.3H₂O (316 mg, 1.00 mmol) in THF (1.0 mL). The resulting mixture was allowed to stir at ambient temperature for 3 hours. The mixture was then diluted with DCM, washed with water, dried over anhydrous MgSO₄, filtered and concentrated in vacuo. The resulting residue was purified by MPLC on silica gel (using a gradient elution of 0-20% MeOH/DCM) to afford the title compound, Example #31.

¹H NMR (600 MHz, acetone-d₆): δ 9.16 (s, 1H), 8.47 (s, 1H), 7.67-7.55 (m, 2H), 7.16 (br s, 1H), 7.05-6.95 (m, 2H), 6.48 (br s, 1H), 4.86-4.69 (m, 1H), 4.02-3.80 (m, 3H), 3.57-3.50 (m, 2H), 3.16 (s, 2H), 3.14-3.08 (m, 2H), 2.70-2.50 (m, 2H), 2.16-2.05 (m, 2H), 1.21-1.12 (m, 3H).

LRMS (ESI) calcd for C₂₁H₂₅FN₆O₄ [M+H]⁺: 445. Found: 445.

1-[1-Acetyl-3-(cyanomethyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide

To a suspension of 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidinium trifluoroacetate (Intermediate #38-2) (50 mg, 0.17 mmol) in DCM (2 mL) was added pyridine (0.050 mL, 0.62 mmol), followed by acetic anhydride (0.030 mL, 0.32 mmol). The reaction mixture was allowed to stir for 30 minutes before the solvent was removed in vacuo. Saturated aqueous NaHCO₃ solution was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 50-100% EtOAc/hexanes followed by 10% MeOH/EtOAc) to afford the title compound, Example #32.

¹H NMR (600 MHz, CDCl₃): δ 8.86 (s, 1H), 8.17 (s, 1H), 7.47 (d, J=7.7 Hz, 2H), 7.33-7.19 (m, 2H), 6.90 (t, J=7.3 Hz, 1H), 5.8 (br s, 2H), 4.55 (dd, J=26.1, 10.1 Hz, 2H), 4.34 (dd, J=26.1, 10.1 Hz, 2H), 3.33-3.18 (m, 2H), 1.90 (s, 3H).

LRMS (ESI) calc'd for C₁₇H₁₈N₆O₂ [M+11]⁺: 339. Found: 339.

1-[4-(Cyanomethyl)-1-propanoylpiperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide

To a suspension of 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-1) (50 mg, 0.11 mmol) in THF (1 mL) was added DIPEA (0.060 mL, 0.34 mmol), followed by propanoyl chloride (0.020 mL, 0.18 mmol). The resulting mixture was allowed to stir for 18 hours before the reaction mixture was concentrated in vacuo to afford an orange oil. The residue was dissolved in DMSO (2 mL) and purified by mass-triggered reverse phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, diluted with saturated aqueous NaHCO₃ and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford the title compound, Example #33-1, as a colorless solid.

¹H NMR (600 MHz, DMSO-d₆): δ 9.04 (s, 1H), 8.48 (s, 1H), 7.54 (br s, 1H), 7.47 (d, J=7.6 Hz, 2H), 7.21 (t, J=7.6 Hz, 2H), 7.14 (br s, 1H), 6.80 (t, J=7.3 Hz, 1H), 4.02-3.96 (m, 1H), 3.75-3.68 (m, 1H), 3.18-3.08 (m, 3H), 2.98-2.90 (m, 1H), 2.45-2.25 (m, 4H), 2.02-1.95 (m, 1H), 1.95-1.85 (m, 1H), 0.94 (t, J=7.3 Hz, 3H).

LRMS (ESI) calc'd for C₂₀H₂₄N₆O₂ [M+H]⁺: 381. Found: 381.

The following compounds shown TABLE 27 were prepared according to Scheme #28 following similar procedures described for Example #33-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 27 Exact Mass Example Structure Compound Name [M + H]⁺ 33-2

1-{1-[(2E)-but-2-enoyl]-4- (cyanomethyl)piperidin-4-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 393, Found 393

1-[4-(Cyanomethyl)-1-(cyclopropylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide

4-[4-Carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-1) (20 mg, 0.05 mmol) was diluted with DMF (0.5 mL) and treated with cyclopropanecarboxylic acid (5 mg, 0.06 mmol), DIPEA (0.020 mL, 0.12 mmol) and 1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (0.040 mL, 0.060 mmol). The reaction mixture was heated to 40° C. and allowed to stir for 16 hours. The mixture was then cooled to ambient temperature, diluted with DMSO (1.0 mL), and purified by reverse-phase preparative HPLC (using a gradient elution of 5-95% MeCN/water, with 0.1% v/v NH₄OH modifier). Desired fractions were identified, combined and concentrated in vacuo to afford the title compound, Example #34-1. ¹H NMR (600 MHz, DMSO-d₆): δ 9.09-9.00 (m, 1H), 8.50 (s, 1H), 7.55 (s, 1H), 7.48 (d, J=7.7 Hz, 2H), 7.26-7.17 (m, 2H), 7.15 (s, 1H), 6.80 (m, 1H), 4.09-3.90 (m, 2H), 3.18 (s, 2H), 2.47 (s, 2H), 2.35 (s, 2H), 2.07-1.97 (m, 2H), 1.95-1.87 (m, 1H), 0.74-0.62 (m, 4H).

LRMS (ESI) calc'd for C₂₁H₂₄N₆O₂ [M+H]⁺: 393. Found: 393.

The following compounds shown TABLE 28 were prepared according to Scheme #28 following similar procedures described for Example #34-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 28 Exact Mass Example Structure Compound Name [M + H]⁺ 34-2

1-[4-(cyanomethyl)-1- (methoxyacetyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 397, Found 397 34-3

1-[4-(cyanomethyl)-1-(2,2- dimethylpropanoyl)piperidin-4-yl]- 3-(phenylamino)-1H-pyrazole-4- carboxamide Calc'd 409, Found 409 34-4

1-[4-(cyanomethyl)-1- pentanoylpiperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 409, Found 409 34-5

1-[4-(cyanomethyl)-1-(N,N- dimethylglycyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 410, Found 410 34-6

1-[4-(cyanomethyl)-1- (tetrahydrofuran-2- ylcarbonyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 423, Found 423 34-7

1-[4-(cyanomethyl)-1- (phenylcarbonyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 429, Found 429 34-8

1-[4-(cyanomethyl)-1-(pyridin-3- ylcarbonyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 430, Found 430 34-9

1-[4-(cyanomethyl)-1-(pyridin-2- ylcarbonyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 430, Found 430 34-10

1-[4-(cyanomethyl)-1-(pyridin-4- ylcarbonyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 430, Found 430 34-11

1-[4-(cyanomethyl)-1-(pyrazin-2- ylcarbonyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 431, Found 431 34-12

1-{4-(cyanomethyl)-1-[(5- methylisoxazol-3- yl)carbonyl]piperidin-4-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 434, Found 434 34-13

1-[4-(cyanomethyl)-1- (cyclohexylcarbonyl)piperidin-4-yl]- 3-(phenylamino)-1H-pyrazole-4- carboxamide Calc'd 435, Found 435 34-14

1-[4-(cyanomethyl)-1-(thiophen-2- ylcarbonyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 435, Found 435 34-15

1-{4-(cyanomethyl)-1-[(2- oxopyrrolidin-1-yl)acetyl]piperidin- 4-yl}-3-(phenylamino)-1H-pyrazole- 4-carboxamide Calc'd 450, Found 450 34-16

1-[4-(cyanomethyl)-1-(thiophen-3- ylcarbonyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 435, Found 435 34-17

1-{4-(cyanomethyl)-1-[(2E)-3- pyridin-3-ylprop-2-enoyl]piperidin- 4-yl}-3-(phenylamino)-1H-pyrazole- 4-carboxamide Calc'd 456, Found 456 34-18

1-{4-(cyanomethyl)-1-[(4- methoxyphenyl)carbonyl]piperidin- 4-yl}-3-(phenylamino)-1H-pyrazole- 4-carboxamide Calc'd 459, Found 459 34-19

1-{1-[(4-chlorophenyl)carbonyl]-4- (cyanomethyl)piperidin-4-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 463, Found 463 34-20

1-{1-[(2-chlorophenyl)carbonyl]-4- (cyanomethyl)piperidin-4-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 463, Found 463 34-21

l-{l-[(3-chlorophenyl)carbonyl]-4- (cyanomethyl)piperidin-4-yl}-3- (phenylamino)-lH-pyrazole-4- carboxamide Calc'd 463, Found 463 34-22

1-[4-(cyanomethyl)-1-(1H-indol-2- ylcarbonyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 468, Found 468 34-23

1-[4-(cyanomethyl)-1-{[4- (dimethylamino)phenyl]carbonyl} piperidin-4-yl]-3-(phenylamino)-lH- pyrazole-4-carboxamide Calc'd 472, Found 472 34-24

1-{4-(cyanomethyl)-1-[(4- methoxyphenyl)acetyl]piperidin-4- yl}-3-(phenylamino)-1H-pyrazole-4- carboxamide Calc'd 473, Found 473 34-25

1-[4-(cyanomethyl)-1-(naphthalene- 1-ylcarbonyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 479, Found 479 34-26

1-{4-(cyanomethyl)-1-[(1-methyl- 1H-indol-2-yl)carbonyl]piperidin-4- yl}-3-(phenylamino)-1H-pyrazole-4- carboxamide Calc'd 482, Found 482 34-27

1-{4-(cyanomethyl)-l-[(3,4- dimethoxyphenyl)carbonyl]piperidin-4- yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 489, Found 489 34-28

1-(4-(cyanomethyl)-1-[(3- morpholin-4- ylphenyl)carbonyl]piperidin-4-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 514, Found 514 34-29

1-[1-(biphenyl-2-ylcarbonyl)-4- (cyanomethyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 505, Found 505 34-30

1-[4-(cyanomethyl)-1-{[4- (trifluoromethyl)phenyl]acetyl} piperidin-4-yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 511, Found 511 34-31

1-{4-(cyanomethyl)-1-[(4- morpholin-4- ylphenyl)carbonyl]piperidin-4-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 514, Found 514 34-32

1-[4-(cyanomethyl)-1-(quinolin-2- ylcarbonyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 480, Found 480 34-33

1-[4-(cyanomethyl)-1- (diphenylacetyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 519, Found 519 34-34

1-[4-(cyanomethyl)-1-{[4-(4- methylpiperazin-1- yl)phenyl]carbonyl}piperidin-4-yl] 3-(phenylamino)-1H-pyrazole-4- carboxamide Calc'd 527, Found 527 34-35

1-[4-(cyanomethyl)-1- (hydroxyacetyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 383, Found 383 34-36

1-[3-(cyanomethyl)-1- propanoylazetidin-3-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 353, Found 353 34-37

1-[3-(cyanomethyl)-1-(2,2- dimethylpropanoyl)azetidin-3-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 381, Found 381 34-38

1-[3-(cyanomethyl)-1-(pyridin-2- ylcarbonyl)azetidin-3-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 402, Found 402 34-39

1-[4-(cyanomethyl)-1- (tetrahydrofuran-2- ylacetyl)piperidin-4-yl]-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 456, Found 456 34-40

1-[4-(cyanomethyl)-1-(2,2- difluoropropanoyl)piperidin-4-yl]-3 [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 436, Found 436 34-41

1-{4-(cyanomethyl)-1-[3-fluoro-2- (fluoromethyl)-2- methylpropanoyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 464, Found 464 34-42

1-[4-(cyanomethyl)-1- (methoxyacetyl)piperidin-4-yl]-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 416, Found 416 34-43

1-[4-(cyanomethyl)-1-(2-hydroxy-2- methylpropanoyl)piperidin-4-yl]-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 430, Found 430 34-44

1-{4-(cyanomethyl)-1-[(1-methyl- 1H-pyrazol-4-yl)carbonyl]piperidin- 4-yl}-3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 452, Found 452 34-45

1-[4-(cyanomethyl)-1- (cyclopropylacetyl)piperidin-4-yl]-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 426, Found 426 34-46

1-{4-(cyanomethyl)-1-[(2R)-2- hydroxy-3- methylbutanoyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 444, Found 444 34-47

1-{4-(cyanomethyl)-1-[(2S)-2- hydroxy-3- methylbutanoyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 444, Found 444 34-48

1-[4-(cyanomethyl)-1-(3,3,3- trifluoro-2- methylpropanoyl)piperidin-4-yl]-3- [(2-fIuoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 468, Found 468 34-49

1-[1-(cyanoacetyl)-4- (cyanomethyl)piperidin-4-yl]-3-[(2- fIuoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 411, Found 411 34-50

1-[4-(cyanomethyl)-1-(3-hydroxy-3- methylbutanoyl)piperidin-4-yl]-3- [(2-fluoropyridin-4-yl)amino]-1H pyrazole-4-carboxamide Calc'd 444, Found 444 34-51

1-[4-(cyanomethyl)-1-{[1- (trifluoromethyl)cyclobutyl]carbonyl} piperidin-4-yl]-3-[(2-fluoropyridin- 4-yl)amino]-1H-pyrazole-4- carboxamide Calc'd 494, Found 494 34-52

1-[4-(cyanomethyl)-1-(1H-imidazol- 1-ylacetyl)piperidin-4-yl]-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 452, Found 452 34-53

1-{4-(cyanomethyl)-1-[(3,3- difluorocyclobutyl)carbonyl]piperidin- 4-yl}-3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 462, Found 462 34-54

1-[4-(cyanomethyl)-1-(3,3- dimethylbutanoyl)piperidin-4-yl]-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 442, Found 442 34-55

1-[4-(cyanomethyl)-1-(3,3,3- trifluoro-2,2- dimethylpropanoyl)piperidin-4-yl]- 3-[(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 482, Found 482 34-56

1-[4-(cyanomethyl)-1-{[1- (trifluoromethyl)cyclopropyl]carbon yl}piperidin-4-yl]-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 480, Found 480 34-57

1-[4-(cyanomethyl)-1-(4,4,4- trifluorobutanoyl)piperidin-4-yl]-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 468, Found 468 34-58

1-{4-(cyanomethyl)-1- [(methylsulfonyl)acetyl]piperidin-4- yl}-3-[(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 464, Found 464 34-59

1-[4-(cyanomethyl)-1-(2,2- difluorobutanoyl)piperidin-4-yl]-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 450, Found 450 34-60

1-{4-(cyanomethyl)-1-[(1- methylcyclobutyl)carbonyl]piperidin- 4-yl}-3-[(2-fluoropyridin-4- yl)amino]-1H-pyrazole-4- carboxamide Calc'd 440, Found 440 34-61

1-[4-(cyanomethyl)-1-(3,3-difluoro- 2-hydroxy-2- methylpropanoyl)piperidin-4-yl]-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 466, Found 466 34-62

1-{4-(cyanomethyl)-1-[(3R)-3- hydroxybutanoyl]piperidin-4-yl}-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 430, Found 430

1-(4-(Cyanomethyl)-1-(3,3,3-trifluoropropanoyl)piperidin-4-yl)-3-(4-fluorophenylamino)-1H-pyrazole-4-carboxamide

3,3,3-Trifluoropropanoic acid (0.009 mL, 0.1 mmol) and HATU (40 mg, 0.11 mmol) were combined in DMF (0.15 mL) and allowed to stir at ambient temperature for 5 minutes. A solution of 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-5) (30 mg, 0.066 mmol) in DMF (0.10 mL) was then added to the reaction mixture, followed by DIPEA (0.045 mL, 0.26 mmol). The resulting solution was allowed to stir at ambient temperature for 16 hours. The mixture was then purified directly by mass-triggered reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier) to afford the title compound, Example #35-1.

¹H NMR (500 MHz, CDCl₃): δ 8.7 (s, 1H), 7.9 (s, 1H), 7.4 (m, J=4.4 Hz, 2H), 7.0 (t, J=8.8 Hz, 2H), 6.0 (br s, 2H), 4.4 (m, 1H), 3.7 (m, 1H), 3.18-3.11 (m, 3H), 3.0 (s, 1H), 2.9 (s, 2H), 2.72-2.64 (m, 2H), 2.05-1.98 (m, 2H).

LRMS (ESI) calc'd for C₂₀H₂₀F₄N₆O₂ [M+H]⁺: 453. Found: 453

The following compounds shown TABLE 29 were prepared according to Scheme #28 following similar procedures described for Example #35-1, which can be achieved by those of ordinary skill in the art of organic synthesis utilizing but not limited to Intermediates #38-4 and 39 as an intermediate.

TABLE 29 Exact Mass Example Structure Compound Name [M + H]⁺ 35-2

1-(4-(cyanomethyl)-1-(3,3,3- trifluoropropanoyl)piperidin-4- yl)-3-(2-fluoropyridin-4- ylamino)-1H-pyrazole-4- carboxamide Calc'd 454, Found 454 35-3

1-(4-(cyanomethyl)-1-(3,3,3- trifluoropropanoyl)piperidin-4- yl)-3-(5-fluoropyridin-3- ylamino)-1H-pyrazole-4- carboxamide Calc'd 454, Found 454

1-[1-(Cyanoacetyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide

To a suspension of 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl) piperidinium trifluoroacetate (60 mg, 0.14 mmol) in Me-THF (2.0 mL) was added DBU (0.065 mL, 0.43 mmol), followed by methyl cyanoacetate (28 mg, 0.29 mmol). The resulting mixture was allowed to stir for 1 hour before saturated aqueous NaHCO₃ solution was added and the resulting mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 50-100%, EtOAc/hexanes followed by elution with 10% MeOH/EtOAc) to afford the title compound, Example #36-1.

¹H NMR (600 MHz, DMSO-d₆): δ 9.04 (s, 1H), 8.49 (s, 1H), 7.50 (t, J=22.0 Hz, 3H), 7.20 (dd, J=26.7, 18.3 Hz, 3H), 6.80 (t, J=7.3 Hz, 1H), 4.15-3.91 (m, 3H), 3.57 (d, J=14.3 Hz, 1H), 3.16 (s, 2H), 3.14-3.05 (m, 1H), 3.02-2.92 (m, 1H), 2.40 (dd, J=28.1, 14.6 Hz, 2H), 2.05 (ddd, J=13.9, 10.2, 4.0 Hz, 1H), 2.00-1.88 (m, 1H).

LRMS (ESI) calc'd for C₂₀H₂₁N₇O₂ [M+H]⁺: 392. Found: 392.

The following compounds shown in TABLE 30 were prepared according to Scheme #28 following similar procedures described for Example 36-1, which can be achieved by those of ordinary skill in the art of organic synthesis utilizing but not limited Intermediate #38-6 as an intermediate.

TABLE 30 Exact Mass Example Structure Compound Name [M + H]⁺ 36-2

1-[1-(cyanoacetyl)-4- (cyanomethyl)piperidin-4-yl]-3-{[4- (methylsulfonyl)phenyl]amino}-1H- pyrazole-4-carboxamide Calc'd 470, Found 470

1-[4-(Cyanomethyl)-1-(isopropylsulfonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide

To a suspension of 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-1) (30 mg, 0.068 mmol) in MeCN (0.50 mL) was added DIPEA (0.030 mL, 0.17 mmol) and DMAP (12 mg, 0.10 mmol). To this mixture was added isopropylsulfonyl chloride (0.008 mL, 0.1 mmol). The resulting mixture was allowed to stir at ambient temperature for 1 hour before it was diluted with DMSO (1.0 mL) and purified directly by reverse-phase preparative HPLC (using a gradient elution of 0-100% MeCN/water, with 0.1% v/v HCOOH modifier). Desired fractions were identified, combined and concentrated in vacuo to afford the title compound, Example #37-1. ¹H NMR (600 MHz, DMSO-d₆): δ 9.03 (s, 1H), 8.47 (s, 1H), 7.54 (br s, 1H), 7.48 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.8 Hz, 2H), 7.15 (br s, 1H), 6.80 (t, J=7.8 Hz, 1H), 3.50-3.56 (m, 2H), 3.19 (s, 2H), 2.98-3.10 (m, 2H), 2.38-2.49 (m, 3H), 2.02-2.08 (m, 2H), 1.15 (d, J=6.6 Hz, 6H). LRMS (ESI) calc'd for C₂₀H₂₆N₆O₃S [M+H]+: 431. Found: 431.

The following compounds shown TABLE 31 were prepared according to Scheme #28 following similar procedures described for Example #37-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 31 Exact Mass Example Structure Compound Name [M + H]⁺ 37-2 

1-[4-(cyanomethyl)-1- (methylsulfonyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 403, Found 403 37-3 

1-[4-(cyanomethyl)-1- (ethylsulfonyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 417, Found 417 37-4 

1-[4-(cyanomethyl)-1-(furan-2- ylsulfonyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 455, Found 455 37-5 

1-{4-(cyanomethyl)-1- [(trifluoromethyl)sulfonyl]piperidin- 4-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 457, Found 457 37-6 

1-[4-(cyanomethyl)-1- (phenylsulfonyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 465, Found 465 37-7 

1-{4-(cyanomethyl)-1-[(1-methyl- 1H-imidazol-4- yl)sulfonyl]piperidin-4-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 469, Found 469 37-8 

1-[1-(benzylsulfonyl)-4- (cyanomethyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 479, Found 479 37-9 

1-{4-(cyanomethyl)-1-[(4- methoxyphenyl)sulfonyl]piperidin- 4-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 495, Found 495 37-10

1-{4-(cyanomethyl)-1-[(3- methoxyphenyl)sulfonyl]piperidin- 4-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 495, Found 495 37-11

1-{1-[(3-chlorophenyl)sulfonyl]-4- (cyanomethyl)piperidin-4-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 499, Found 499 37-12

1-{1-[(2-chlorophenyl)sulfonyl]-4- (cyanomethyl)piperidin-4-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 499, Found 499 37-13

1-[4-(cyanomethyl)-1-{[4- (trifluoromethyl)phenyl]sulfonyl} piperidin-4-yl]-3-(phenylamino)- 1H-pyrazole-4-carboxamide Calc'd 533, Found 533 37-14

1-[1-(biphenyl-4-ylsulfonyl)-4- (cyanomethyl)piperidin-4-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 541, Found 541 37-15

1-[4-(cyanomethyl)-1- (cyclopropylsulfonyl)piperidin-4- yl]-3-(phenylamino)-1H-pyrazole- 4-carboxamide Calc'd 429, Found 429 37-16

1-[3-(cyanomethyl)-1- (methylsulfonyl)azetidin-3-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 375, Found 375 37-17

1-[3-(cyanomethyl)-1-(furan-2- ylsulfonyl)azetidin-3-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 427, Found 427 37-18

1-{3-(cyanomethyl)-1- [(trifluoromethyl)sulfonyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 429, Found 429 37-19

1-[3-(cyanomethyl)-1- (phenylsulfonyl)azetidin-3-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 437, Found 437 37-20

1-[1-(benzylsulfonyl)-3- (cyanomethyl)azetidin-3-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 451, Found 451

1-{3-(Cyanomethyl)-1-[(3-fluorophenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H pyrazole-4-carboxamide

3-[4-Carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidinium trifluoroacetate (Intermediate #38-2) (25 mg, 0.060 mmol) was dissolved in MeCN (0.50 mL) and treated with DIPEA (0.020 mL, 0.12 mmol) and 1-fluoro-3-isocyanatobenzene (0.010 mL, 0.090 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and then diluted with DMSO (1.0 mL) and purified directly by reverse-phase preparative HPLC (using a gradient elution of 5-95% MeCN/water, with 0.1% v/v NH₄OH modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #38-1.

¹H NMR (600 MHz, DMSO-d₆) δ 9.09 (s, 1H), 8.92 (s, 1H), 8.55 (s, 1H), 7.62-7.56 (m, 1H), 7.50-7.46 (m, 3H), 7.25-7.18 (m, 5H), 6.81 (s, 1H), 6.73 (s, 1H), 4.36 (d, J=9.3, 2H), 4.30 (d, J=9.3, 2H), 3.59 (s, 2H). LRMS (ESI) calc'd for C₂₂H₂₀FN₇O₂ [M+H]⁺: 434. Found: 434.

The following compounds shown in TABLE 32 were prepared according to Scheme #28 following similar procedures described for Example #38-1, which can be achieved by those of ordinary skill in the art of organic synthesis utilizing but not limited to Intermediates #38-1, 38-2, 38-3, and 38-7 as intermediates.

TABLE 32 Exact Mass Example Structure Compound Name [M + H]⁺ 38-2 

1-[3-(cyanomethyl)-1- (cyclohexylcarbamoyl)azetidin- 3-yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 422, Found 422 38-3 

1-{3-(cyanomethyl)-1-[(1- methylethyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 382, Found 382 38-4 

1-{3-(cyanomethyl)-1-[(3,4- dimethylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 444, Found 444 38-5 

1-[1-(butylcarbamoyl)-3- (cyanomethyl)azetidin-3-yl]-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 396, Found 396 38-6 

1-{3-(cyanomethyl)-1-[(4- methylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 430, Found 430 38-7 

1-[3-(cyanomethyl)-1-{[4-(1- methylethyl)phenyl]carbamoyl} azetidin-3-yl-3-(phenylamino)- 1H-pyrazole-4-carboxamide Calc'd 458, Found 458 38-8 

1-[3-(cyanomethyl)-1-{[2-(1- methylethyl)phenyl]carbamoyl} azetidin-3-yl]-3-(phenylamino)- 1H-pyrazole-4-carboxamide Calc'd 458, Found 458 38-9 

ethyl N-({3-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1-yl]- 3-(cyanomethyl)azetidin-1- yl}carbonyl)alaninate Calc'd 440, Found 440 38-10

1-{3-(cyanomethyl)-1-[(2,5- difluorophenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 452, Found 452 38-11

1-{3-(cyanomethyl)-1-[(3- methylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 430, Found 430 38-12

1-{3-(cyanomethyl)-1-[(2,4,6- trimethylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 458, Found 458 38-13

1-{1-[(3-chloro-4- methylphenyl)carbamoyl]-3- (cyanomethyl)azetidin-3-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 464, Found 464 38-14

1-{1-[(4-chloro-2- methylphenyl)carbamoyl]-3- (cyanomethyl)azetidin-3-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 464, Found 464 38-15

1-{3-(cyanomethyl)-1-[(4- cyanophenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 441, Found 441 38-16

1-{3-(cyanomethyl)-1-[(2,5- dimethylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 444, Found 444 38-17

1-{1-[(5-chloro-2- methylphenyl)carbamoyl]-3- (cyanomethyl)azetidin-3-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 464, Found 464 38-18

1-[3-(cyanomethyl)-1- (propylcarbamoyl)azetidin-3-yl]- 3-(phenylamino)-1H-pyrazole-4- carboxamide Calc'd 382, Found 382 38-19

1-{3-(cyanomethyl)-1-[(2,4- dimethylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 444, Found 444 38-20

1-{3-(cyanomethyl)-1-[(3,5- dimethylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 444, Found 444 38-21

1-{3-(cyanomethyl)-1-[(3,4- difluorophenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 452, Found 452 38-22

1-{1-[(3-chloro-2- methylphenyl)carbamoyl]-3- (cyanomethyl)azetidin-3-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 464, Found 464 38-23

1-{3-(cyanomethyl)-1-[(2-ethyl- 6- methylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 458, Found 458 38-24

1-{1-[(2-chloro-6- methylphenyl)carbamoyl]-3- (cyanomethyl)azetidin-3-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 464, Found 464 38-25

1-{3-(cyanomethyl)-1-[(2- methoxy-5- methylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 460, Found 460 38-26

1-{3-(cyanomethyl)-1-[(4- ethoxyphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 460, Found 460 38-27

1-{3-(cyanomethyl)-1-[(2- methylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 430, Found 430 38-28

1-{3-(cyanomethyl)-1-[(2,4- difluorophenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 452, Found 452 38-29

1-{3-(cyanomethyl)-1-[(1,1,3,3- tetramethylbutyl)carbamoyl] azetidin-3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 452, Found 452 38-30

1-{3-(cyanomethyl)-1-[(2- ethoxyphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 460, Found 460 38-31

1-{3-(cyanomethyl)-1-[(2,6- dimethylphenyl)carbamoyl] azetidin-3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 444, Found 444 38-32

1-{1-[(3- acetylphenyl)carbamoyl]-3- (cyanomethyl)azetidin-3-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 458, Found 458 38-33

1-[3-(cyanomethyl)-1-{[(1R)-1- phenylethyl]carbamoyl}azetidin- 3-yl]-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 444, Found 444 38-34

1-{3-(cyanomethyl)-1-[(4- ethylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 444, Found 444 38-35

1-{3-(cyanomethyl)-1-[(3- ethylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 444, Found 444 38-36

1-{3-(cyanomethyl)-1-[(4- methoxy-2- methylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 460, Found 460 38-37

1-{3-(cyanomethyl)-1-[(3-fluoro- 4- methylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 448, Found 448 38-38

1-{3-(cyanomethyl)-1-[(5-fluoro- 2- methylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 448, Found 448 38-39

1-{3-(cyanomethyl)-1-[(2- ethylphenyl)carbamoyl]azetidin- 3-yl}-3-(phenylamino)-1H- pyrazole-4-carboxamide Calc'd 444, Found 444 38-40

1-{1-[(3-chloro-4- fluorophenyl)carbamoyl]-3- (cyanomethyl)azetidin-3-yl}-3- (phenylamino)-1H-pyrazole-4- carboxamide Calc'd 468, Found 468 38-41

1-{3-(cyanomethyl)-1-[(4- methylphenyl)carbamoyl]azetidin- 3-yl}-3-{[4- (methylsulfonyl)phenyl]amino}- 1H-pyrazole-4-carboxamide Calc'd 508, Found 508 38-42

1-{3-(cyanomethyl)-1-[(2,5- difluorophenyl)carbamoyl] azetidin-3-yl}-3-{[4- (methylsulfonyl)phenyl]amino}- 1H-pyrazole-4-carboxamide Calc'd 530, Found 530 38-43

1-[1-(butylcarbamoyl)-3- (cyanomethyl)azetidin-3-yl]-3- {[4- (methylsulfonyl)phenyl]amino}- 1H-pyrazole-4-carboxamide Calc'd 474, Found 474 38-44

4-(4-carbamoyl-3-(4- (trifluoromethylsulfonyl) phenylamino)-1H-pyrazol-1-yl)- 4-(cyanomethyl)-N- isopropylpiperidine-1- carboxamide Calc'd 542, Found 542 38-45

4-(4-carbamoyl-3-(4- (trifluoromethylsulfonyl) phenylamino)-1H-pyrazol-1-yl)-4- (cyanomethyl)-N-(4- cyanophenyl)piperidine-1- carboxamide Calc'd 601, Found 601 38-46

4-[4-Carbamoyl-3- (phenylamino)-1H-pyrazol-1-yl]- 4-(cyanomethyl)-N-(1- methylethyl)piperidine-1- carboxamide Calc'd 410, Found 410 38-47

4-[4-carbamoyl-3- (phenylamino)-1H-pyrazol-1-yl]- 4-(cyanomethyl)-N-(4- cyanophenyl)piperidine-1- carboxamide Calc'd 469, Found 469

Cis or trans 3-((4-chlorophenyl)amino)-1-(1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxamide

Step A. 3-Amino-1-(1-(cyanomethyl)-4-oxocyclohexyl)-1H-pyrazole-4-carboxamide

Aqueous hydrochloric acid (1 N, 36 mL, 36 mmol) was added to a solution of 3-amino-1-(8-(cyanomethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole-4-carboxamide (Intermediate 35-5) (5.5 g, 18 mmol) in THF (106 mL). The reaction vessel was capped with a reflux condenser and heated to 80° C. for 2 hours. The reaction mixture was then cooled to ambient temperature, diluted with ethyl acetate, and neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was separated and then washed with brine. The washed solution was dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated to afford the title compound, which was used without further purification.

LRMS (ESI) calc'd for C₁₄H₂₉N₅O₃ [M+H]⁺: 262. Found: 262.

Step B. Cis or trans 3-amino-1-(1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxamide

Sodium cyanoborohydride (962 mg, 15.3 mmol) was added to a solution of 3-amino-1-(1-(cyanomethyl)-4-oxocyclohexyl)-1H-pyrazole-4-carboxamide (1.6 g, 6.1 mmol), 3-fluoroazetidine hydrochloride (1.71 g, 15.3 mmol), and triethylamine (2.13 mL, 15.3 mmol) in tetrahydrofuran (30 mL) and methanol (30 mL) at 23° C. The reaction mixture was stirred for 1 hour at 23° C., then was concentrated. The residue was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate solution. The organic layer was washed with brine, and the washed solution was dried over anhydrous sodium sulfate. The dried solution was filtered, and the filtrate was concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 5 to 15% MeOH/EtOAc) to afford the title compound.

LRMS (ESI) calc'd for C₁₅H₂₂FN₆O [M+H]⁺: 321. Found: 321.

Step C. Cis or trans 3-((4-chlorophenyl)amino)-1-(1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxamide

Nitrogen was sparged through a mixture of cis or trans 3-amino-1-(1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxamide (50 mg, 0.16 mmol), 1-bromo-4-chlorobenzene (60 mg, 0.31 mmol), potassium acetate (31 mg, 0.31 mmol), and Me₄-^(t)Bu-X-Phos (30 mg, 0.062 mmol) in isopropanol (1.0 mL) in a reaction vessel for 5 minutes, and then Pd₂(dba)₃ (29 mg, 0.031 mmol) was added. The reaction vial was sealed, and heated to 85° C. After 2 hours, the reaction mixture was cooled to ambient temperature. The cooled reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, the washed solution was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated and the residue was purified by MPLC on silica gel (using a gradient elution of 80-100% EtOAc/hexanes) to afford the title compound, Example #39-1.

LRMS (ESI) calc'd for C₂₁H₂₅ClFN₆O [M+H]⁺: 431. Found: 431.

The following compound shown in TABLE 33 were prepared according to Scheme #34 following similar procedures described for Example #39-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 33 Exact Mass Example Structure Compound Name [M + H]⁺ 39-2

1-[1-(cyanomethyl)-4-(3- fluoroazetidin-1-yl)cyclohexyl]-3- {[4- (trifluoromethyl)phenyl]amino}-1H- pyrazole-4-carboxamide Calc'd 465, found 465

Cis or trans 1-(1-(cyanomethyl)-4-(cyclohexylamino)cyclohexyl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide

Step A: 1-(1-(Cyanomethyl)-4-oxocyclohexyl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide (Example 40-1A)

A solution of 1-[8-(cyanomethyl)-1,4-dioxaspiro[4.5]dec-8-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide (Example 6-6) (150 mg, 0.376 mmol) in 1:3 ratio of 1N aqueous HCl/THF (0.6 mL/1.8 mL) was heated at 75° C. for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc and saturated aqueous NaHCO₃. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous MgSO₄, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford Intermediate 36-A. ¹H NMR (600 MHz, acetone-d₆): δ 9.18 (s, 1H), 8.59 (s, 1H), 7.61-7.63 (m, 2H), 7.20 (brs, 1H), 7.01 (t, J=8.4 Hz, 2H), 6.54 (brs, 1H), 3.22 (s, 2H), 2.88-2.95 (m, 2H), 2.40-2.51 (m, 4H), 2.34-2.37 (m, 2H). LRMS (ESI) calc'd for C₁₈H₁₉FN₅O₂ [M+H]⁺: 356. Found: 356.

Step B: Cis or trans 1-(1-(cyanomethyl)-4-(cyclohexylamino)cyclohexyl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide

Cyclohexanamine (0.026 mL, 0.22 mmol) was added to a mixture of 1-(1-(cyanomethyl)-4-oxocyclohexyl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide (40 mg, 0.11 mmol) in MeOH (0.31 mL) and DMF (0.062 mL). The reaction mixture was allowed to stir at 60° C. for 15 minutes. Sodium cyanoborohydride (7 mg, 0.1 mmol) was added to the reaction mixture and allowed to stir at 60° C. for 24 hours. The mixture was then purified directly by mass-triggered reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier) to afford a diastereometric mixture of the title compound. 1-(1-(cyanomethyl)-4-((2,4-difluorophenyl)amino)cyclohexyl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide was chirally resolved to the constituent diastereomers by chiral SFC (Chiral Technology IB-H, 2.1×25 cm, 30% MeOH/70% CO₂, 70 mL/min). Desired fractions were identified, combined, and concentrated in vacuo to afford diastereomerically pure samples of the title compounds:

Example #40-1

Cis or trans 1-(1-(cyanomethyl)-4-(cyclohexylamino)cyclohexyl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide, first diastereomer to elute from column.

¹H NMR (600 MHz, DMSO-d₆): δ 9.02 (s, 1H), 8.49 (s, 1H), 7.58 (br s, 1H), 7.52-7.50 (m, 2H), 7.12 (br s, 1H), 7.04 (t, J=8.4 Hz, 2H), 3.32-3.31 (m, 114), 2.98 (s, 2H), 2.58-2.55 (m, 2H), 2.47-2.46 (m, 1H), 1.85-1.80 (m, 6H), 1.65-1.63 (m, 2H), 1.54-1.52 (m, 1H), 1.20-1.03 (m, 8H).

LRMS (ESI) calc'd for C₂₄H₃₁FN₆O [M+H]⁺: 439. Found: 439.

Example #40-2

Cis or trans 1-(1-(cyanomethyl)-4-(cyclohexylamino)cyclohexyl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide, second diastereomer to elute from column.

¹H NMR (600 MHz, DMSO-d₆): δ 9.02 (s, 1H), 8.40 (s, 1H), 7.57 (br s, 1H), 7.53-7.51 (m, 2H), 7.11 (br s, 1H), 7.03 (t, J=9 Hz, 2H), 3.32-3.31 (m, 1H), 3.17 (s, 2H), 2.47-2.46 (m, 1H), 2.25 (m, 2H), 1.99-1.96 (m, 2H), 1.87 (m, 4H), 1.69-1.67 (m, 2H), 1.56-1.54 (m, 3H), 1.23-1.20 (m, 3H), 1.10-1.02 (m, 3H).

LRMS (ESI) calc'd for C₂₄H₃₁FN₆O [M+H]⁺: 439. Found: 439.

The following compounds shown in TABLE 34 were prepared according to Scheme #36 following similar procedures described for Example #40-1 and 40-2, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 34 Exact Exam- Mass ple Structure Compound Name [M + H]⁺ 40-3 

Cis or trans 1-{1-(cyanomethyl)-4-[(3- fluorophenyl)amino]cyclohexyl}-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 451, Found 451 40-4 

Cis or trans 1-[1-(cyanomethyl)-4- (pyridin-2-ylamino)cyclohexyl]-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 435, Found 435 40-5 

Cis or trans 1-[1-(cyanomethyl)-4- (tetrahydro-2H-pyran-4- ylamino)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 441, Found 441 40-6 

Cis or trans 1-[1-(cyanomethyl)-4- (pyridin-3-ylamino)cyclohexyl]-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 435, Found 435 40-7 

Cis or trans 1-{1-(cyanomethyl)-4-[(4- hydroxyphenyl)amino]cyclohexyl}-3- ({4-[(difluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazole-4-carboxamide Calc'd 545, Found 545 40-8 

Cis or trans 1-[1-(cyanomethyl)-4- (pyridin-3-ylamino)cyclohexyl]-3-({4- [(difluoromethyl)sulfonyl]phenyl}amino)- 1H-pyrazole-4-carboxamide Calc'd 530, Found 530 40-9 

Cis or trans 1-[1-(cyanomethyl)-4- (pyridin-3-ylamino)cyclohexyl]-3-({4- [(difluoromethyl)sulfonyl]phenyl}amino)- 1H-pyrazole-4-carboxamide Calc'd 530, Found 530 40-10

Cis or trans 1-{1-(cyanomethyl)-4-[(2,5- difluorophenyl)amino]cyclohexyl}-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 470, Found 470 40-11

Cis or trans 1-{4-[(2- chlorophenyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 468, Found 468 40-12

Cis or trans 1-[1-(cyanomethyl)-4- (pyridin-2-ylamino)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 434, Found 40-13

Cis or trans 1-[1-(cyanomethyl)-4-(4- hydroxypiperidin-1-yl)cyclohexyl]-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 442, Found 442 40-14

Cis or trans 1-{1-(cyanomethyl)-4-[(3- hydroxyphenyl)amino]cyclohexyl}-3- ({4-[(difluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazole-4-carboxamide Calc'd 545, Found 545 40-15

Cis or trans 1-{1-(cyanomethyl)-4- [methyl(phenyl)amino]cyclohexyl}-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 448, Found 448 40-16

Cis or trans 1-{1-(cyanomethyl)-4-[(3- fluorophenyl)amino]cyclohexyl}-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 451, Found 451 40-17

Cis or trans 1-{1-(cyanomethyl)-4-[(2- fluorophenyl)amino]cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 452, Found 452 40-18

Cis or trans 1-{1-(cyanomethyl)-4-[(4- fluorophenyl)amino]cyclohexyl}-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 451, Found 451 40-19

Cis or trans 1-{1-(cyanomethyl)-4-[(4- fluorophenyl)amino]cyclohexyl}-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 451, Found 451 40-20

Cis or trans 1-{1-(cyanomethyl)-4-[(3,4- difluorophenyl)amino]cyclohexyl}-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 470, Found 470 40-21

Cis or trans 1-[1-(cyanomethyl)-4-(2,3- dihydro-1H-indol-1-yl)cyclohexyl]-3- [(4-fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 459, Found 459 40-22

Cis or trans 1-[1-(cyanomethyl)-4- (pyridin-2-ylamino)cyclohexyl]-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 435, Found 435 40-23

Cis or trans 1-[1-(cyanomethyl)-4- (cyclohexylamino)cyclohexyl]-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 440, Found 440 40-24

Cis or trans 1-{1-(cyanomethyl)-4-[(2- fluorophenyl)amino]cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 452, Found 452 40-25

Cis or trans 1-{4-[(2- chlorophenyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 468, Found 468 40-26

Cis or trans 1-[1-(cyanomethyl)-4- (tetrahydro-2H-pyran-4- ylamino)cyclohexyl]-3-({4- [(difluoromethyl)sulfonyl]phenyl}amino)- 1H-pyrazole-4-carboxamide Calc'd 537, Found 537 40-27

Cis or trans 1-[1-(cyanomethyl)-4-(4- hydroxypiperidin-1-yl)cyclohexyl]-3- [(4-fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 441, Found 441 40-28

Cis or trans 1-[1-(cyanomethyl)-4- (cyclohexylamino)cyclohexyl]-3-({4- [(difluoromethyl)sulfonyl]phenyl}amino)- 1H-pyrazole-4-carboxamide Calc'd 535, Found 535 40-29

Cis or trans 1-{4-[(3- chlorophenyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 468, Found 468 40-30

Cis or trans 1-[1-(cyanomethyl)-4-(2,3- dihydro-1H-indol-1-yl)cyclohexyl]-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 460, Found 460 40-31

Cis or trans 1-[1-(cyanomethyl)-4-(4,4- difluoropiperidin-1-yl)cyclohexyl]-3- ({4-[(difluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazole-4-carboxamide Calc'd 557, Found 557 40-32

Cis or trans 1-{1-(cyanomethyl)-4-[(2- hydroxyphenyl)amino]cyclohexyl}-3- ({4-[(difluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazole-4-carboxamide Calc'd 545, Found 545 40-33

Cis or trans 1-{1-(cyanomethyl)-4-[(2,4- difluorophenyl)amino]cyclohexyl}-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 470, Found 470 40-34

Cis or trans 1-{1-(cyanomethyl)-4- [methyl(phenyl)amino]cyclohexyl}-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 448, Found 448 40-35

Cis or trans 1-{1-(cyanomethyl)-4-[(3,4- difluorophenyl)amino]cyclohexyl}-3- [(4-fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 469, Found 469 40-36

Cis or trans 1-{1-(cyanomethyl)-4-[(3,4- difluorophenyl)amino]cyclohexyl}-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 470, Found 470 40-37

Cis or trans 1-{1-(cyanomethyl)-4-[(2,4- difluorophenyl)amino]cyclohexyl}-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 470, Found 470 40-38

Cis or trans 1-[1-(cyanomethyl)-4- (tetrahydro-2H-pyran-4- ylamino)cyclohexyl]-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 442, Found 442 40-39

Cis or trans 1-[1-(cyanomethyl)-4- (pyridin-3-ylamino)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 434, Found 434 40-40

Cis or trans 1-{1-(cyanomethyl)-4-[(4- fluorophenyl)amino]cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 452, Found 452 40-41

Cis or trans 1-[1-(cyanomethyl)-4-(4- hydroxypiperidin-1-yl)cyclohexyl]-3- [(4-fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 441, Found 441 40-42

Cis or trans 1-[1-(cyanomethyl)-4-(4,4- difluoropiperidin-1-yl)cyclohexyl]-3- ({4-[(difluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazole-4-carboxamide Calc'd 557, Found 557 40-43

Cis or trans 1-[1-(cyanomethyl)-4-(4- hydroxypiperidin-1-yl)cyclohexyl]-3- ({4-[(difluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazole-4-carboxamide Calc'd 537, Found 537 40-44

Cis or trans 1-{1-(cyanomethyl)-4-[(3- hydroxyphenyl)amino]cyclohexyl}-3- ({4-[(difluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazole-4-carboxamide Calc'd 545, Found 545 40-45

Cis or trans 1-{4-[(4- chlorophenyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 468, Found 468 40-46

Cis or trans 1-{4-[(3- chlorophenyl)aminol-1- (cyanomethyl)cyclohexyl}-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 467, Found 467 40-47

Cis or trans 1-{1-(cyanomethyl)-4-[(4- fluorophenyl)amino]cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 452, Found 452 40-48

Cis or trans 1-{1-(cyanomethyl)-4-[(2- hydroxyphenyl)amino]cyclohexyl}-3- ({4-[(difluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazole-4-carboxamide Calc'd 545, Found 545 40-49

Cis or trans 1-[1-(cyanomethyl)-4-(2,3- dihydro-1H-indol-1-yl)cyclohexyl]-3- [(4-fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 459, Found 459 40-50

Cis and trans 1-{1-(cyanomethyl)-4- [(2,5-difluorophenyl)amino]cyclohexyl}-3- [(4-fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 469, Found 469 40-51

Cis or trans 1-[1-(cyanomethyl)-4- (cyclohexylamino)cyclohexyl]-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 440, Found 440 40-52

Cis or trans 1-{4-[(4- chlorophenyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 467, Found 467 40-53

Cis or trans 1-{4-[(4- chlorophenyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 467, Found 467 40-54

Cis or trans 1-[1-(cyanomethyl)-4-(2,3- dihydro-1H-indol-1-yl)cyclohexyl]-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 460, Found 460 40-55

Cis or trans 1-{1-(cyanomethyl)-4-[(3- fluorophenyl)amino]cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 452, Found 452 40-56

Cis or trans 1-[1-(cyanomethyl)-4-(4- hydroxypiperidin-1-yl)cyclohexyl]-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 442, Found 442 40-57

Cis or trans 1-[1-(cyanomethyl)-4- (cyclohexylamino)cyclohexyl]-3-({4- [(difluoromethyl)sulfonyl]phenyl}amino)- 1H-pyrazole-4-carboxamide Calc'd 535, Found 535 40-58

Cis or trans 1-{1-(cyanomethyl)-4-[(2- fluorophenyl)amino]cyclohexyl}-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 451, Found 451 40-59

Cis or trans 1-{1-(cyanomethyl)-4-[(4- hydroxyphenyl)amino]cyclohexyl}-3- ({4-[(difluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazole-4-carboxamide Calc'd 545, Found 545 40-60

Cis or trans 1-{1-(cyanomethyl)-4-[(2- fluorophenyl)amino]cyclohexyl}-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 451, Found 451 40-61

Cis or trans 1-{4-[(4- chlorophenyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 468, Found 468 40-62

Cis or trans 1-{4-[(3- chlorophenyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 468, Found 468 40-63

Cis or trans 1-{1-(cyanomethyl)-4-[(2,5- difluorophenyl)amino]cyclohexyl}-3- [(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 470, Found 470 40-64

Cis or trans 1-{1-(cyanomethyl)-4-[(3- fluorophenyl)amino]cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 452, Found 452 40-65

Cis or trans 1-[1-(cyanomethyl)-4- (tetrahydro-2H-pyran-4- ylamino)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 441, Found 441 40-66

Cis or trans 1-[1-(cyanomethyl)-4- (tetrahydro-2H-pyran-4- ylamino)cyclohexyl]-3-({4- [(difluoromethyl)sulfonyl]phenyl}amino)- 1H-pyrazole-4-carboxamide Calc'd 537, Found 537 40-67

Cis or trans 1-[1-(cyanomethyl)-4-(4- hydroxypiperidin-1-yl)cyclohexyl]-3- ({4-[(difluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazole-4-carboxamide Calc'd 537, Found 537 40-68

Cis or trans 1-{1-(cyanomethyl)-4-[(2- hydroxyethyl)amino]cyclohexyl}-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 401, found 401 40-69

Cis or trans 1-{1-(cyanomethyl)-4- [(cyclopropylmethyl)amino]cyclohexyl}- 3-[(4-fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 411, found 411 40-70

Cis or trans 1-[1-(cyanomethyl)-4-(4,4- difluoropiperidin-1-yl)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 461, found 461 40-71

Cis or trans 1-{1-(cyanomethyl)-4-[(2- methoxyethyl)amino]cyclohexyl}-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 415, found 415 40-72

Cis or trans 1-[1-(cyanomethyl)-4- {methyl[2-(methylsulfonyl)ethyl] amino}cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole- 4-carboxamide Calc'd 477, found 477 40-73

Cis or trans 1-[1-(cyanomethyl)-4-{[4- (trifluoromethyl)phenyl]amino}cyclohexyl]- 3-[(4-fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 501, found 501 40-74

Cis or trans 1-[1-(cyanomethyl)-4-(3- methoxyazetidin-1-yl)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 427, found 427 40-75

Cis or trans 1-[1-(cyanomethyl)-4- (pyridin-3-ylamino)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 434, found 434 40-76

Cis or trans 1-[4-(4-acetylpiperazin-1- yl)-1-(cyanomethyl)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 468, found 468 40-77

Cis or trans 1-{1-(cyanomethyl)-4-[(2,2- difluoroethyl)amino]cyclohexyl}-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 421, found 421 40-78

Cis or trans 1-[1-(cyanomethyl)-4- (methylamino)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 371, found 371 40-79

Cis or trans 1-{1-(cyanomethyl)-4-[(2- fluoroethyl)amino]cyclohexyl}-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 403, found 403 40-80

Cis or trans 1-[4-azetidin-1-yl-1- (cyanomethyl)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 397, found 397 40-81

Cis or trans 1-[1-(cyanomethyl)-4-(3- methoxyazetidin-1-yl)cyclohexyl]-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 428, found 428 40-82

Cis or trans 1-[1-(cyanomethyl)-4-(3- fluoroazetidin-1-yl)cyclohexyl]-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 416, found 416 40-83

Cis or trans 1-[1-(cyanomethyl)-4- (phenylamino)cyclohexyl]-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 434, found 434 40-84

Cis or trans 1-{1-(cyanomethyl)-4-[(2,2- difluoroethyl)amino]cyclohexyl}-3-({4- [(difluoromethyl)sulfonyl]phenyl}amino)- 1H-pyrazole-4-carboxamide Calc'd 517, found 517 40-85

Cis or trans 1-{1-(cyanomethyl)-4- [(2,2,2-trifluoroethyl)amino] cyclohexyl}-3-({4-[(difluoromethyl) sulfonyl]phenyl}amino)-1H- pyrazole-4-carboxamide Calc'd 535, found 535 40-86

Cis or trans 1-[1-(cyanomethyl)-4- (phenylamino)cyclohexyl]-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 434, found 434 40-87

Cis or trans 1-{1-(cyanomethyl)-4-[(2,2- difluoroethyl)amino]cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 422, found 422 40-88

Cis or trans 1-[1-(cyanomethyl)-4- (phenylamino)cyclohexyl]-3-({4- [(difluoromethyl)sulfonyl]phenyl}amino)- 1H-pyrazole-4-carboxamide Calc'd 529, found 529 40-89

Cis or trans 1-{1-(cyanomethyl)-4- [(2,2,2-trifluoroethyl)amino]cyclohexyl}- 3-({4-[(difluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazole-4-carboxamide Calc'd 535, found 535 40-90

Cis or trans 1-[1-(cyanomethyl)-4-(1,3- dihydro-2H-isoindol-2-yl)cyclohexyl]-3- [(4-fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 459, found 459 40-91

Cis or trans 1-[1-(cyanomethyl)-4-(3- fluoroazetidin-1-yl)cyclohexyl]-3-({4- [(difluoromethyl)sulfonyl]phenyl}amino)- 1H-pyrazole-4-carboxamide Calc'd 511, found 511 40-92

Cis or trans 1-[4-(benzylamino)-1- (cyanomethyl)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 447, found 447 40-93

Cis or trans 1-{1-(cyanomethyl)-4- [(2,2,2-trifluoroethyl)amino]cyclohexyl}- 3-[(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 440, found 440 40-94

Cis or trans 1-[1-(cyanomethyl)-4-(3- methoxyazetidin-1-yl)cyclohexyl]-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 428, found 428 40-95

Cis or trans 1-{1-(cyanomethyl)-4- [(2,2,2-trifluoroethyl)amino]cyclohexyl}- 3-[(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 440, found 440 40-96

Cis or trans 1-[1-(cyanomethyl)-4- (phenylamino)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 433, found 433 40-97

Cis or trans 1-{4-[(4- cyanobenzyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 472, found 472 40-98

Cis or trans 1-{1-(cyanomethyl)-4- [(2,2,2-trifluoroethyl)amino]cyclohexyl}- 3-[(4-fluorophenyl)amino]-1H- pyrazole-4-carboxamide Calc'd 439, found 439 40-99

Cis or trans 1-{1-(cyanomethyl)-4-[(2,2- difluoroethyl)amino]cyclohexyl}-3-({4- [(difluoromethyl)sulfonyl]phenyl}amino)- 1H-pyrazole-4-carboxamide Calc'd 517, found 517  40-100

Cis or trans 1-[1-(cyanomethyl)-4-(3- fluoroazetidin-1-yl)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 415, found 415  40-101

Cis or trans 1-{1-(cyanomethyl)-4- [(2,2,2-trifluoroethyl)amino]cyclohexyl}- 3-[(4-fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 439, found 439  40-102

Cis or trans 1-[1-(cyanomethyl)-4- (phenylamino)cyclohexyl]-3-({4- [(difluoromethyl)sulfonyl]phenyl}amino)- 1H-pyrazole-4-carboxamide Calc'd 529, found 529  40-103

Cis or trans 1-[1-(cyanomethyl)-4- (phenylamino)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 433, found 433  40-104

Cis or trans 1-[1-(cyanomethyl)-4-(3- fluoroazetidin-1-yl)cyclohexyl]-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 416, found 416  40-105

Cis or trans 1-[1-(cyanomethyl)-4-(3- fluoroazetidin-1-yl)cyclohexyl]-3-({4- [(difluoromethyl)sulfonyl]phenyl}amino)- 1H-pyrazole-4-carboxamide Calc'd 511, found 511  40-106

Cis or trans 1-{1-(cyanomethyl)-4-[(2,2- difluoroethyl)amino]cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H-pyrazole- 4-carboxamide Calc'd 422, found 422  40-107

Cis or trans 1-[1-(cyanomethyl)-4-(3- fluoroazetidin-1-yl)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 415, found 415  40-108

1-[cis-4-(benzylamino)-1- (cyanomethyl)cyclohexyl]-3-[(4- fluorophenyl)amino]-1H-pyrazole-4- carboxamide Calc'd 447, found 447

Trans 1-(1-(cyanomethyl)-4-((2,4-difluorobenzyl)amino)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (Example 41-1)

Step A: Cis or trans 1-(4-amino-1-(cyanomethyl)cyclohexyl)-3-((2-fluoropyridin-4yl)amino)-1H-pyrazole-4-carboxamide (Example 41-1A and 41-1B)

To a solution of 1-(1-(cyanomethyl)-4-oxocyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (1.5 g, 4.2 mmol) in MeOH (11.7 mL) and DMF (9.1 mL) was added NH₄OAc (3.24 g, 42.1 mmol). The reaction mixture was allowed to stir at ambient temperature for 15 minutes. Sodium cyanoborohydride (0.265 g, 4.21 mmol) was added and the reaction mixture was allowed to stir for 20 hours at room temperature. The mixture was then purified directly by mass-triggered reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier) to afford a diasteromeric mixture of the title compound. 1-(4-Amino-1-(cyanomethyl)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide was chirally resolved to the constituent diastereomers by chiral SFC (Phenomenex Lux Cellulose-4, 5 μM, 2.1×25 cm, 30% MeOH+0.25% dimethyl ethylamine/70% CO₂, 70 mL/min). Desired fractions were identified, combined, and concentrated in vacuo to afford diastereomerically pure samples of the title compounds:

Example #41-1A

Cis 1-(4-amino-1-(cyanomethyl)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide, first diastereomer to elute from column.

¹H NMR (500 MHz, DMSO-d₆): δ 10.10 (br s, 1H), 9.67 (s, 1H), 8.70 (s, 1H), 7.93-7.91 (m, 2H), 7.78 (br s, 1H), 7.36-7.32 (m, 2H), 3.06-3.02 (m, 2H), 2.69 (d, J=4 Hz, 2H), 2.63-2.60 (m, 2H), 1.94-1.89 (m, 2H), 1.32-1.26 (m, 1H), 1.18 (t, J=7.5 Hz, 3H).

LRMS (ESI) calc'd for C₁₇H₂₀FN₇O [M+H]⁺: 358. Found: 358.

Example #41-1B

Trans 1-(4-amino-1-(cyanomethyl)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide, second diastereomer to elute from column.

¹H NMR (500 MHz, DMSO-d₆): δ 9.67 (s, 1H), 8.54 (s, 1H), 7.93-7.91 (m, 2H), 7.73 (br s, 1H), 7.37-7.31 (m, 3H), 3.21 (s, 2H), 3.14 (m, 1H), 2.62 (m, 1H), 2.34-2.30 (m, 2H), 2.09-2.05 (m, 2H), 1.87-1.83 (m, 2H), 1.67-1.63 (m, 2H).

LRMS (ESI) calc'd for C₁₇H₂₀FN₇O [M+H]⁺: 358. Found: 358.

Step B: Trans 1-(1-(cyanomethyl)-4-((2,4-difluorobenzyl)amino)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (Example 41-1)

To a solution of trans 1-(4-amino-1-(cyanomethyl)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (10 mg, 0.028 mmol) in MeOH (0.23 mL) and DMF (0.047 mL) was added 2,4-difluorobenzaldehyde (0.003 mL, 0.028 mmol). The reaction mixture was allowed to stir at ambient temperature for 15 minutes. Sodium cyanoborohydride (2 mg, 0.03 mmol) was added and the reaction mixture was allowed to stir for 20 hours at ambient temperature. The mixture was then purified directly by mass-triggered reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier) to afford the title compound.

¹H NMR (500 MHz, acetone-d₆): δ 9.62 (s, 1H), 8.49 (s, 1H), 7.89 (d, J=6 Hz, 1H), 7.67 (s, 1H), 7.51 (dd, J=15, 7.8 Hz, 1H), 7.34 (s, 1H), 7.28-7.25 (m, 2H), 7.15-7.11 (m, 1H), 7.03-7.01 (m, 1H), 3.69 (s, 2H), 3.15 (s, 2H), 2.58-2.56 (m, 1H), 2.23 (m, 2H), 2.02 (m, 2H), 1.82-1.80 (m, 1H), 1.63 (m, 2H), 1.51 (m, 2H). LRMS (ESI) calc'd for C₂₄H₂₄FN₇O [M+H]⁺: 484. Found: 484.

The following compounds shown in TABLE 35 were prepared according to Scheme #35 following similar procedures described for Example #41-1, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 35 Exact Mass Example Structure Compound Name [M + H]⁺ 41-2 

1-[trans-4-amino-1- (cyanomethyl)cyclohexyl]-3-({4- (difluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazole-4-carboxamide Calc'd 453, Found 453 41-3 

1-[cis-4-amino-1- (cyanomethyl)cyclohexyl]-3-({4- (difluoromethyl)sulfonyl]phenyl} amino)-1H-pyrazole-4-carboxamide Calc'd 453, Found 453 41-4 

Cis or trans 1-{1-(cyanomethyl)-4- [(2,4- difluorobenzyl)amino]cyclohexyl}- 3-[(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 484, Found 484 41-5 

Cis or trans 1-{1-(cyanomethyl)-4- [(3- hydroxybenzyl)amino]cyclohexyl}- 3-[(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 464, Found 464 41-6 

Cis or trans 1-{4-[(4- cyanobenzyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 473, Found 473 41-7 

Cis or trans 1-{1-(cyanomethyl)-4- [(2- hydroxybenzyl)amino]cyclohexyl}- 3-[(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 464, Found 464 41-8 

Trans 1-{1-(cyanomethyl)-4- [(cyclohexylmethyl)amino]cyclohexyl}- 3-[(2-fluoropyridin-4-yl)amino]- 1H-pyrazole-4-carboxamide Calc'd 454, Found 454 41-9 

Cis or trans 1-{4-[(4- chlorobenzyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 482, Found 482 41-10

Cis or trans 1-{4-[(2- chlorobenzyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 482, Found 482 41-11

Cis or trans 1-{1-(cyanomethyl)-4- [(2-fluorobenzyl)amino]cyclohexyl}- 3-[(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 466, Found 466 41-12

Cis or trans 1-{1-(cyanomethyl)-4- [(4-fluorobenzyl)amino]cyclohexyl}- 3-[(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 466, Found 466 41-13

Cis or trans 1-{1-(cyanomethyl)-4- [(pyridin-4- ylmethyl)amino]cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 449, Found 449 41-14

Cis or trans 1-{4-[(3- cyanobenzyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 473, Found 473 41-15

Cis or trans 1-{4-[(4- chlorobenzyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 482, Found 482 41-16

Cis or trans 1-{4-[(2- chlorobenzyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 482, Found 482 41-17

Cis or trans 1-{1-(cyanomethyl)-4- [(pyridin-2- ylmethyl)amino]cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 449, Found 449 41-18

Cis or trans 1-[4-(benzylamino)-1- (cyanomethyl)cyclohexyl]-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 448, Found 448 41-19

Cis or trans 1-{1-(cyanomethyl)-4- [(3-fluorobenzyl)amino]cyclohexyl}- 3-[(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 466, Found 466 41-20

Cis or trans 1-{4-[(3- chlorobenzyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 482, Found 482 41-21

Cis or trans 1-{1-(cyanomethyl)-4- [(2-fluorobenzyl)amino]cyclohexyl}- 3-[(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 466, Found 466 41-22

Cis or trans 1-{1-(cyanomethyl)-4- [(pyridin-3- ylmethyl)amino]cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 449, Found 449 41-23

Cis or trans 1-{4-[(3- chlorobenzyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 482, Found 482 41-24

Cis or trans 1-{1-(cyanomethyl)-4- [(3-fluorobenzyl)amino]cyclohexyl}- 3-[(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 466, Found 466 41-25

Cis or trans 1-{1-(cyanomethyl)-4- [(4-fluorobenzyl)amino]cyclohexyl}- 3-[(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 466, Found 466 41-26

Cis or trans 1-{1-(cyanomethyl)-4- [(4- hydroxybenzyl)amino]cyclohexyl}- 3-[(2-fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 464, Found 464 41-27

Cis or trans 1-{4-[(2- cyanobenzyl)amino]-1- (cyanomethyl)cyclohexyl}-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 473, Found 473 41-28

Cis or trans 1-[4-(benzylamino)-1- (cyanomethyl)cyclohexyl]-3-[(2- fluoropyridin-4-yl)amino]-1H- pyrazole-4-carboxamide Calc'd 448, Found 448

cis-1-(1-(Cyanomethyl)-4-(3-fluorophenylsulfonamido)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide

To a solution of cis-1-(4-amino-1-(cyanomethyl)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (12 mg, 0.026 mmol) in DMF (0.26 mL) was added DIPEA (0.018 mL, 0.105 mmol) and DMAP (4 mg, 0.03 mmol). 3-Fluorobenzenesulfonyl chloride (0.005 mL. 0.04 mmol) was added and the reaction mixture was allowed to stir at ambient temperature for 20 hours. The mixture was then purified directly by mass-triggered reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo. The residue was dissolved in a 1:1 mixture of MeOH/DMF and passed through a macroporous polystyrene-carbonate cartridge. The cartridge was washed with 1:1 MeOH/DMF, and the filtrate was concentrated in vacuo to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆): δ 9.64 (s, 1H), 8.53 (s, 1H), 7.93 (br s, 1H), 7.90 (d, J=6 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.68 (br s, 1H), 7.64-7.62 (m, 2H), 7.57-7.55 (m, 1H), 7.52-7.47 (m, 1H), 7.32-7.30 (m, 3H), 3.15-3.13 (m, 1H), 2.98 (s, 2H), 2.62-2.61 (m, 1H), 1.83 (t, J=13 Hz, 2H), 1.59-1.57 (m, 2H), 1.16-1.09 (m, 2H).

LRMS (ESI) calc'd for C₂₃H₂₃F₂N₇O₃S [M+H]⁺: 516. Found: 516.

1-((3S,4R or 3R,4S)-4-(Cyanomethyl)-1-(2,2-difluoropronanoyl)-3-fluoropiperidin-4-yl)-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazole-4-carboxamide

Step A: (3S,4R and 3R,4S)-tert-Butyl 4-(4-carbamoyl-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate and (3S,4S and 3R,4R)-tert-butyl 4-(4-carbamoyl-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate

To a solution of tert-butyl (4E and 4Z)-4-(cyanomethylidene)-3-fluoropiperidine-1-carboxylate (158 mg, 0.656 mmol) in MeCN were added 3-[(6-fluoropyridin-3-yl)amino]-1H-pyrazole-4-carboxamide (145 mg, 0.656 mmol) and DBU (0.20 mL, 1.3 mmol). The solution was heated to 65° C. for 16 hours. Another batch of (4E and 4Z)-4-(cyanomethylidene)-3-fluoropiperidine-1-carboxylate (790 mg, 3.28 mmol) was added and stirred for another 2 hours at ambient temperature. The reaction mixture was diluted with EtOAc and washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo to afford an oily residue. The residue was purified by MPLC on silica gel (using a gradient elution of 0-100% EtOAc/hexanes) to afford the title compounds.

Example 43-1-A1

(3S,4R and 3R,4S)-tert-Butyl 4-(4-carbamoyl-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate

LRMS (ESI) calc'd for C₂₁H₂₆F₂N₇O₃ [M+H]⁺: 462. Found: 462.

Example 43-1-A2

(3S,4S and 3R,4R)-tert-butyl 4-(4-carbamoyl-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate

LRMS (ESI) calc'd for C₂₁H₂₆F₂N₇O₃ [M+11]⁺: 462. Found: 462.

Step B: (3S,4R and 3R,4S)-4-(4-carbamoyl-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidin-1-ium

To a solution of (3S,4R and 3R,4S)-tert-Butyl 4-(4-carbamoyl-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate (100 mg, 0.217 mmol) in DCM (1 mL) was added TFA (1 mL) and stirred for 30 min. The reaction mixture was then concentrated in vacuo and used without further purification.

LRMS (ESI) calc'd for C₁₆H₁₇F₂N₇O [M+H]⁺: 362. Found: 362.

Step C: 1-((3S,4R or 3R,4S)-4-(Cyanomethyl)-1-(2,2-difluoropronanoyl)-3-fluoropiperidin-4-yl)-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazole-4-carboxamide

(3S,4R and 3R,4S)-4-(4-carbamoyl-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidin-1-ium (33 mg, 0.069 mmol) was dissolved in DMF (1 mL) and TEA (0.058 mL, 0.42 mmol), was added followed by 2,2-difluoropropanoic acid (23 mg, 0.21 mmol), and 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (32 mg, 0.083 mmol). The resulting mixture was stirred for 16 hours. The reaction mixture was filtered and purified directly by reverse phase HPLC followed by chiral SFC to afford the chirally resolved title compound.

Example 43-1

First enantiomer to elute: 1-((3S,4R or 3R,4S)-4-(cyanomethyl)-1-(2,2-difluoropropanoyl)-3-fluoropiperidin-4-yl)-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazole-4-carboxamide. ¹H NMR (500 MHz, CD₃OD): δ 8.51 (d, J=11.5 Hz, 1H), 8.34 (s, 1H), 8.16 (m, 1H), 7.10-6.98 (dd, J=11, 2 Hz, 1H) 5.68-5.56 (dd, J=45, 13 Hz, 1H), 4.73-4.31 (m 2H), 3.46-3.00 (m, 4H), 2.66 (t, J=13 Hz, 1H), 2.40-2.30 (m, 1H), 1.86-1.77 (m, 3H).

LRMS (ESI) calc'd for C₁₉H₂₀F₄N₇O₂ [M+H]⁺: 454. Found: 454.

Example 43-2

Second enantiomer to elute: 1-((3S,4R or 3R,4S)-4-(cyanomethyl)-1-(2,2-difluoropropanoyl)-3-fluoropiperidin-4-yl)-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazole-4-carboxamide. ¹H NMR (500 MHz, CD₃OD): 8.51 (d, J=11.5 Hz, 1H), 8.34 (s, 1H), 8.16 (m, 1H), 7.10-6.98 (dd, J=11, 2 Hz, 1H) 5.68-5.56 (dd, J=45, 13 Hz, 1H), 4.73-4.31 (m 2H), 3.46-3.00 (m, 4H), 2.66 (t, J=13 Hz, 1H), 2.40-2.30 (m, 1H), 1.86-1.77 (m, 3H).

LRMS (ESI) calc'd for C₁₉H₂₀F₄N₇O₂ [M+H]⁺: 454. Found: 454.

The following compounds shown in TABLE 36 were prepared according to Scheme #28 following similar procedures described for Example #43-1 and 43-2, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 36 Exact Mass Example Structure Compound Name [M + H]⁺ 43-3

1-((3R,4R or 3S,4S)-4- (cyanomethyl)-1-(2,2- difluoropropanoyl)-3- fluoropiperidin-4-yl)-3-((6- fluoropyridin-3-yl)amino)-1H- pyrazole-4-carboxamide Calc'd 454, Found 454 43-4

1-((3R,4R or 3S,4S)-4- (cyanomethyl)-1-(2,2- difluoropropanoyl)-3- fluoropiperidin-4-yl)-3-((6- fluoropyridin-3-yl)amino)-1H- pyrazole-4-carboxamide Calc'd 454, Found 454

Cis or trans 1-[1-(cyanomethyl)-4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide

Step A: 1-[1-(Cyanomethyl)-4-hydroxycyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide

To a solution of 1-[1-(cyanomethyl)-4-oxocyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide (90 mg, 0.25 mmol) in a mixture of THF (1.9 mL)/MeOH (0.6 mL) at 0° C. was added NaBH₄ (10 mg, 0.25 mmol), and the mixture was stirred at 0° C. for 10 minutes, then warmed to ambient temperature and stirred for another 10 minutes. The mixture was diluted with EtOAc and H₂O. The organic layer was separated, washed with saturated aqueous NH₄Cl, brine, dried over anhydrous MgSO₄, and concentrated in vacuo. The crude residue containing a mixture of the two diasteromeric alcohols was used for next step without purification. LRMS (ESI) calc'd for C₁₈H₂₀FN₅O₂ [M+H]⁺: 358. Found: 358.

Step 2: 1-[4-Azido-1-(cyanomethyl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide

To a solution of 1-[1-(cyanomethyl)-4-hydroxycyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide (75 mg, 0.21 mmol) in DCM (2 mL) at ambient temperature was added TEA (0.059 mL, 0.42 mmol), and methanesulfonyl chloride (0.020 mL, 0.25 mmol). The mixture was stirred at ambient temperature for 10 minutes. The mixture was diluted with saturated aqueous NaHCO₃, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous MgSO₄ and concentrated in vacuo. The crude residue (90 mg, 0.207 mmol) was diluted in DMF (1.0 mL), NaN₃ (27 mg, 0.41 mmol) was added and the mixture was heated at 90° C. for 16 hours. The mixture was cooled to ambient temperature, diluted with H₂O and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous MgSO₄ and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 30-100% EtOAc/hexanes) to give the title compound as a mixture of two diasteromers (ratio 1:3), which was used without further purification.

LRMS (ESI) calc'd for C₁₈H₂₀FN₈O [M+H]⁺: 383. Found: 383.

Step C: Cis or Trans 1-[1-(cyanomethyl)-4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide

To a solution of 1-[4-azido-1-(cyanomethyl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide (60 mg, 0.16 mmol) in ethanol (0.8 mL) was added cyclopropylacetylene (0.013 mL, 0.16 mmol) and a mixture of sodium ascorbate (16 mg, 0.080 mmol) and CuSO₄ 5H₂O (16 mg, 0.060 mmol) in H₂O (0.8 mL) The heterogenous mixture was stirred vigorously at ambient temperature for 16 hours. The mixture was diluted with 2N ammonia and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO₄, and filtered. To the filtrate was added a spoon of silica gel and the volatiles were removed in vacuo. The resulting powder was subjected to MPLC purification (using a gradient elution of 40-100% EtOAc/hexanes followed by 10% MeOH/hexanes) to give the title compound as a mixture of two diasteromers (ratio 2:3). Further purification using chiral SFC (Chiral tech. IB-H 2.1×25 cm, eluting with 30% MeOH/CO₂) afforded the two pure diastereomers.

Example 44-1

1^(st) diastereomer to elute: cis or Trans 1-[1-(cyanomethyl)-4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide LRMS (ESI) calc'd for C₂₃H₂₆FN₈O [M+H]⁺: 449. Found: 449.

Example 44-2

2^(nd) diastereomer to elute: cis or Trans 1-[1-(cyanomethyl)-4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide LRMS (ESI) calc'd for C₂₃H₂₆FN₈O [M+H]⁺: 449. Found: 449.

Cis or trans 1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)carbamoyl]cyclohexyl}-3-(phenylamino)-1H-pyrazole-4-carboxamide

To a solution of tert-butyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)cyclohexanecarboxylate (290 mg, 0.685 mmol) in DCM (3 mL) at ambient temperature was added TFA (1.0 mL), and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated in vacuo, and the residue was taken up in DMF (8 mL). To an aliquot (1.6 mL) of this solution was added DIPEA (0.071 mL, 0.41 mmol), 2,2,2-trifluoroethylamine hydrochloride (26 mg, 0.19 mmol), HOBT (29 mg, 0.19 mmol), and EDC (37 mg, 0.19 mmol). The mixture was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with saturated aqueous NaHCO₃ and extracted with EtOAc. The organic layer was separated, dried over anhydrous MgSO₄, filtered and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier) to afford the two pure disastereomers.

Example 45-1

1^(st) diastereomer to elute, cis or trans 1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)carbamoyl]cyclohexyl}-3-(phenylamino)-1H-pyrazole-4-carboxamide

¹H NMR (600 MHz, DMSO-d₆): δ 9.06 (s, 1H), 8.46 (t, J=7.2 Hz, 1H), 8.40 (s, 1H), 7.59 (brs, 1H), 7.47 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.8 Hz, 2H), 7.13 (brs, 1H), 6.79 (t, J=7.8 Hz, 1H), 3.76-3.83 (m, 2H), 3.0 (s, 2H), 2.58 (d, J=13.2 Hz, 2H), 2.25-2.30 (m, 1H), 1.78 (td, J=7.8, 3.6 Hz, 2H), 1.67-1.69 (m, 2H), 1.28-1.35 (m, 2H). LRMS (ESI) calc'd for C₂₁H₂₄F₃N₆O₂ [M+H]⁺: 449. Found: 449.

Example 45-2

2^(nd) diastereomer to elute, cis or trans 1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)carbamoyl]cyclohexyl}-3-(phenylamino)-1H-pyrazole-4-carboxamide. 2. ¹H NMR (600 MHz, DMSO-d₆): δ 9.06 (s, 1H), 8.48 (t, J=6.0 Hz, 1H), 8.41 (s, 1H), 7.56 (brs, 1H), 7.48 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.8 Hz, 2H), 7.11 (brs, 1H), 6.79 (t, J=7.8 Hz, 1H), 3.84-3.92 (m, 2H), 3.22 (s, 2H), 2.32-2.46 (m, 2H), 2.25 (d, J=13.2 Hz, 2H), 1.92-1.97 (m, 2H), 1.74-1.77 (m, 2H), 1.64-1.72 (m, 2H).

LRMS (ESI) calc'd for C₂₁H₂₄F₃N₆O₂ [M+H]⁺: 449. Found: 449.

(3S,4S and 3R,4R)-2,2-Difluoroethyl 4-(4-carbamoyl-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate

Step A: tert-Butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate

To a solution of tert-butyl (4E and 4Z)-4-(cyanomethylidene)-3-fluoropiperidine-1-carboxylate (800 mg, 3.33 mmol) in MeCN (10 mL) were added 3-amino-1H-pyrazole-4-carboxamide (350 mg, 2.78 mmol) and DBU (0.837 mL, 5.55 mmol). The solution was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with EtOAc and washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The oily residue was purified by MPLC on silica gel (0-100% EtOAc/hexanes) to afford the title compound as a mixture of diastereomers. LRMS (ESI) calc'd for C₁₆H₂₃FN₆O₃ [M+H]⁺: 367. Found: 367.

Step B: tert-Butyl 4-(4-carbamoyl-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate

To a solution of tert-butyl 4-(4-carbamoyl-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate (514 mg, 1.40 mmol) in dioxane (10 mL) were added 4-bromo-2-fluoropyridine (247 mg, 1.40 mmol) tetramethyl-t-butyl X-Phos (135 mg, 0.281 mmol), potassium phosphate tribasic (893 mg, 4.21 mmol), and Pd₂dba₃ (128 mg, 0.140 mmol). The solution was degassed by bubbling nitrogen gas and heated to 90° C. for 16 hours. The reaction was cooled to ambient temperature, diluted with EtOAc, washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-100% MeOH/DCM) to afford the title compound as a mixture of diasteromers. LRMS (ESI) calc'd for C₂₁H₂₆F₂N₇O₃ [M+H]⁺: 462. Found: 462

Step C: 1-(4-(Cyanomethyl)-3-fluoropiperidin-4-yl1)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide

To a solution of tert-butyl 4-(4-carbamoyl-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate (127 mg, 0.275 mmol) in DCM (3 mL) was added TFA (1 mL) and stirred for 30 min. The solution was quenched with saturated aqueous.NaHCO₃ and extracted with EtOAc. The organic layer was dried over anhydrous MgSO₄, filtered, and concentrated in vacuo to afford the title compound. This crude residue was used without further purification.

Step D: (3S,4S and 3R,4R)-2,2-Difluoroethyl 4-(4-carbamoyl-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate

To a solution of 1,1′-[carbonylbis(oxy)]dipyrrolidine-2,5-dione (51 mg, 0.20 mmol) in MeCN (0.5 mL) were added TEA (0.093 mL, 0.66 mmol) and 2,2-difluoroethanol (16 mg, 0.20 mmol). The resulting mixture was stirred for 2 hours at ambient temperature. 1-(4-(Cyanomethyl)-3-fluoropiperidin-4-yl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (60 mg, 0.17 mmol) dissolved in DMSO (0.3 mL) and MeCN (0.5 mL) was added to the mixed carbonate solution and heated to 65° C. for 16 hours. The mixture was filtered and purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier) to afford the title compound. LRMS (ESI) calc'd for C₁₉H₁₉F₄N₇O₃ [M+H]⁺: 470. Found: 470.

CHIRAL CHROMATOGRAPHY

The following experimental procedures exemplify the chiral chromatography and isolation of enantiopure or diastereomerically pure Examples of the instant invention. The following Examples are for illustrative purposes only and are not intended to limit the scope of the instant invention in any way.

Cis-1-(4-amino-1-(cyanomethyl)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide or Trans-1-(4-amino-1-(cyanomethyl)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide (Examples 41-1A and 41-1B)

1-(4-amino-1-(cyanomethyl)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide was separated to the constituent diastereomers by chiral SFC (Chiral Technology IA-H, 2.1×25 cm, 30% MeOH+0.25% dimethyl ethylamine/70% CO₂, 65 mL/min). Desired fractions were identified, combined, and concentrated in vacuo to afford diastereomerically pure samples of the title compounds:

Example #41-1A

Cis-1-(4-amino-1-(cyanomethyl)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide, first diastereomer to elute from column.

¹H NMR (600 MHz, DMSO-d₆): δ 9.64 (s, 1H), 8.56 (s, 1H), 7.89 (d, J=5.4, 1H), 7.70 (br s, 1H), 7.34-7.29 (m, 3H), 3.01 (s, 2H), 2.81 (m, 1H), 2.57-2.50 (m, 2H), 1.84 (t, J=13.2 Hz, 2H), 1.77-1.75 (m, 2H), 1.19-1.07 (m, 4H).

LRMS (ESI) calc'd for C₁₇H₂₀FN₇O [M+H]⁺: 358. Found: 358.

Example #41-1B

Trans-1-(4-amino-1-(cyanomethyl)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide, second diastereomer to elute from column.

¹H NMR (600 MHz, DMSO-d₆): δ 9.64 (s, 1H), 8.49 (s, 1H), 7.89 (d, 1H), 7.68 (br s, 1H), 7.36-7.29 (m, 3H), 6.91 (br s, 2H), 3.18 (s, 2H), 3.12-3.09 (m, 1H), 2.28-2.26 (m, 2H), 2.04 (t, J=10.8 Hz, 2H), 1.84-1.82 (m, 2H), 1.61-1.55 (m, 2H).

LRMS (ESI) calc'd for C₁₇H₂₀FN₇O [M+H]⁺: 358. Found: 358.

The following compounds shown in TABLE 37 were separated using a procedure similar to that reported above for Examples 41-1A and 41-1B, which can be achieved by those of ordinary skill in the art of organic synthesis.

TABLE 37 Exact Mass Example Structure Compound Name [M + H]⁺ 41-2

Cis-4-amino-1- (cyanomethyl)cyclohexyl)- 3-((4- ((difluoromethyl)sulfonyl) phenyl)amino)-1H- pyrazole-4-carboxamide Calc'd 453, Found 453 41-3

Trans-4-amino-1- (cyanomethyl)cyclohexyl)- 3-((4- ((difluoromethyl)sulfonyl) phenyl)amino)-1H- pyrazole-4-carboxamide Calc'd 453, Found 453 47-3

tert-butyl (3R,4S or 3S,4R)-4-{4-carbamoyl-3- [(4-fluorophenyl)amino]- 1H-pyrazol-1-yl}-4- (cyanomethyl)-3- fluoropiperidine-1- carboxylate Calc'd 461, Found 461 47-4

tert-butyl (3S,4R or 3R,4S)-4-{4-carbamoyl-3- [(4-fluorophenyl)amino]- 1H-pyrazol-1-yl}-4- (cyanomethyl)-3- fluoropiperidine-1- carboxylate Calc'd 461, Found 461

tert-Butyl (3S,4R or 3R,4S)-4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)-3-methylpiperidine-1-carboxylate

tert-Butyl (3S,4R and 3R,4S)-4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)-3-methylpiperidine-1-carboxylate was chirally resolved to the two constituent enantiomers by chiral SFC (Chiral Technology IC-H, 2.1×25 cm, 25% MeOH—CO₂, 100 mL/min, 35° C., 100 bar). Desired fractions were identified, combined, and concentrated in vacuo to afford enantiomerically pure samples of the title compounds:

Example 48-1

First-eluting enantiomer, tert-Butyl (3S,4R or 3R,4S)-4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)-3-methylpiperidine-1-carboxylate.

¹H-NMR data is consistent with spectral data reported for the racemic mixture, Example #2-10.

LRMS (ESI) calc'd for C₂₃H₃₁N₆O₃ [M+H]⁺: 439. Found: 439.

Example 48-2

Second-eluting enantiomer, tert-Butyl (3S,4R or 3R,4S)-4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)-3-methylpiperidine-1-carboxylate.

¹H-NMR data is consistent with spectral data reported for the racemic mixture, Example #2-10

LRMS (ESI) calc'd for C₂₃H₃₁N₆O₃ [M+H]⁺: 439. Found: 439.

(3S or 3R)-Tetrahydrofuran-3-yl 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate

(3S and 3R)-Tetrahydrofuran-3-yl 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate was chirally resolved by to the constituent enantiomers by chiral SFC (Chiral Technology IB-H, 2.1×25 cm, 20% MeOH+0.25% isobutylamine/CO₂, 70 mL/min). Desired fractions were identified, combined, and concentrated in vacuo to afford enantiomerically pure samples of the title compounds:

Example 49-1

(3S or 3R)-tetrahydrofuran-3-yl 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate, first enantiomer to elute from column.

¹H NMR (600 MHz, acetone-d₆): δ 9.76 (s, 1H), 8.56 (s, 1H), 7.93 (d, J=5.7 Hz, 1H), 7.39 (s, 1H), 7.35-7.22 (m, 2H), 6.64 (br s, 1H), 5.19-5.15 (m, 1H), 3.93-3.87 (m, 2H), 3.83-3.77 (m, 2H), 3.75-3.66 (m, 2H), 3.25-3.12 (m, 4H), 2.66-2.60 (m, 2H), 2.19-1.91 (m, 4H).

LRMS (ESI) calc'd for C₂₁H₂₄FN₇O₄ [M+H]⁺: 458. Found: 458.

Example 49-2

(3S or 3R)-tetrahydrofuran-3-yl 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate, second enantiomer to elute from column.

¹H NMR (600 MHz, acetone-d₆): δ 9.76 (s, 1H), 8.56 (s, 1H), 7.93 (d, J=5.7 Hz, 1H), 7.39 (s, 1H), 7.35-7.22 (m, 2H), 6.64 (br s, 1H), 5.19-5.15 (m, 1H), 3.93-3.87 (m, 2H), 3.83-3.77 (m, 2H), 3.75-3.66 (m, 2H), 3.25-3.12 (m, 4H), 2.66-2.60 (m, 2H), 2.19-1.91 (m, 4H).

LRMS (ESI) calc'd for C₂₁H₂₄FN₇O₄ [M+11]⁺: 458. Found: 458.

(3S or 3R)-tetrahydrofuran-3-yl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate

(3S and 3R)-Tetrahydrofuran-3-yl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate was chirally resolved to the constituent enantiomers by chiral SFC (Chiral Technology OD-H, 2.1×25 cm, 20% 2-propanol/CO₂, 70 mL/min). Desired fractions were identified, combined, and concentrated in vacuo to afford enantiomerically pure samples of the title compounds:

Example 50-1

(3S or 3R)-tetrahydrofuran-3-yl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate, first enantiomer to elute from column.

¹H NMR (600 MHz, acetone-d₆): δ 9.16 (s, 1H), 8.47 (s, 1H), 7.67-7.55 (m, 2H), 7.15 (br s, 1H), 7.05-6.96 (m, 2H), 6.48 (br s, 1H), 5.19-5.15 (m, 1H), 3.93-3.87 (m, 2H), 3.82-3.77 (m, 2H), 3.76-3.66 (m, 2H), 3.22-3.08 (m, 4H), 2.65-2.58 (m, 2H), 2.17-2.06 (m, 2H), 1.99-1.90 (m, 2H).

LRMS (ESI) calc'd for C₂₂H₂₅FN₆O₄ [M+H]⁺: 457. Found: 457.

Example 50-2

(3S or 3R)-tetrahydrofuran-3-yl4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate, second enantiomer to elute from column.

¹H NMR (600 MHz, acetone-d₆): 9.16 (s, 1H), 8.47 (s, 1H), 7.67-7.55 (m, 2H), 7.15 (br s, 1H), 7.05-6.96 (m, 2H), 6.48 (br s, 1H), 5.19-5.15 (m, 1H), 3.93-3.87 (m, 2H), 3.82-3.77 (m, 2H), 3.76-3.66 (m, 2H), 3.22-3.08 (m, 4H), 2.65-2.58 (m, 2H), 2.17-2.06 (m, 2H), 1.99-1.90 (m, 2H).

LRMS (ESI) calc'd for C₂₂H₂₅FN₆O₄ [M+H]⁺: 457. Found: 457.

BIOLOGICAL ASSAYS

Jak Biochemical HTRF Assay Protocol

The ability of compounds to inhibit the activity of JAK1, JAK2, JAK3, and Tyk2 was measured using a recombinant purified GST-tagged catalytic domain for each enzyme (Invitrogen JAK1 #M4290, JAK2 #M4290, JAK3 #M4290, Tyk2 #M4290) in an HTRF format biochemical assay. The reactions employed a common peptide substrate, LCB-EQEDEPEGDYFEWLW-NH₂ (in-house). The basic assay protocol is as follows: First, 250 nL of diluted compounds in DMSO were dispensed into the wells of a dry 384-well Black plate (Greiner #781076) using a Labcyte Echo 555 acoustic dispenser. Subsequent reagent additions employed an Agilent Bravo. Next, 18 μL of 1.11× enzyme and 1.11× substrate in 1× assay buffer (Invitrogen kinase buffer # PV3189, 2 mM DTT, 0.05% BSA) were added to the wells and shaken and then preincubated for 30 minutes at room temperature to allow compound binding to equilibrate. After equilibration, 2 μL of 10×ATP in 1× assay buffer was added to initiate the kinase reaction and the plates were shaken and then incubated at room temperature for 120 minutes. At the end of the incubation, 20 μL of 2× stop buffer (streptavidin-Dylight 650 (Thermo #84547B/100 mL), Eu-tagged pY20 antibody (Perkin Elmer #AD0067), EDTA, HEPES, and Triton) was added to quench the reaction. Plates were shaken and centrifuged and then incubated 60 minutes at room temperature and then read on a Perkin Elmer Envision (λ_(ex)=337 nm, λ_(em)=665 and 615 nm, TRF delay time=20 μs). HTRF signal=10,000*665 nm reading/615 nm reading. After normalization to untreated controls, the percent inhibition of the HTRF signal at each compound concentration was calculated. The plot of percent inhibition versus the log of compound concentration was fit with a 4-parameter dose response equation to calculate IC₅₀ values.

Final Reaction Conditions were:

[E] [S] [ATP] [Eu-pY20] [SA-Dylight] Enzyme (nM) (μM) (μM) (nM) (nM) JAK1 1.405 0.75 31.8 9 312.5 JAK2 0.052 0.75 8.5 9 312.5 JAK3 0.031 0.75 2.9 9 312.5 Tyk2 2.612 0.75 6.9 9 312.5 Compound concentrations tested were 1496, 499, 175, 49.9, 18.7, 6.2, 2.1, 0.75, 0.24, 0.075, and 0.0125 nM, with 1.25% residual DMSO.

BIOLOGICAL DATA

Examples of the instant invention were evaluated in JAK1 and JAK2 in vitro binding assays as described above. The following table tabulates the JAK1 IC₅₀ values and JAK2 IC₅₀ values disclosed for the instant invention.

Example JAK1 IC₅₀ JAK2 IC₅₀  1 67 1481 2-1 1 27 2-2 0.5 23 2-3 8 57 2-4 0.5 18 2-5 0.6 7 2-6 0.5 1 2-7 0.3 10 2-8 2 5 2-9 1 21  2-10 2 21  2-11 29 614  2-12 115 404  2-13 27 38  2-14 20 193  2-15 10 92  2-16 0.2 2  2-17 2 27  2-18 3 91  2-19 12 267  2-20 33 241  2-21 31 405  2-22 13 127  2-23 198 1481 3-1 4 154 3-2 6 414 3-3 5 488 3-4 8 174 3-5 0.2 4 3-6 0.2 5 3-7 0.3 22 3-8 1 54 3-9 1 37  3-10 3 47  3-11 4 74  3-12 2 40  3-13 0.7 21  3-14 2 49  3-15 191 >1496  3-16 45 861  3-17 32 780  3-18 3 89  3-19 0.6 18  3-20 5 102  3-21 0.6 20  3-22 0.4 12  3-23 33 559  3-24 0.1 2  3-25 0.7 21  3-26 0.2 3  3-27 1 24  3-28 0.6 26  3-29 9 209  3-30 0.3 6  3-31 1 44  3-32 204 >1496  3-33 7 102  3-34 5 215  3-35 19 280  3-36 3 46  3-37 0.6 17  3-38 2 37  3-39 4 117  3-40 3 67  3-41 213 >1496  3-42 12 287  3-43 10 295  3-44 0.2 6  3-45 2 70  3-46 3 78  3-47 13 181  3-48 1 26  3-49 5 147  3-50 3 39  3-51 0.06 0.6  3-52 0.4 8  3-53 0.4 9  3-54 0.3 4  3-55 1 75  3-56 1 23 4-1 0.1 1 4-2 2 20 4-3 0.6 11 4-4 0.5 23 4-5 22 183 4-6 3 38 5-1 34 162 5-2 271 738 6-3 1 25 6-4 0.05 0.2 6-5 13 133 6-6 7 48 6-7 19 206  7 8 113  8 50 813 9-1 0.2 5 9-2 0.3 9 9-3 0.8 21 9-4 0.1 2 9-5 0.2 6 9-6 0.8 3 9-7 0.5 2 9-8 0.3 3 9-9 0.4 6  9-10 0.2 3  9-11 0.2 3  9-12 0.5 6  9-13 3 138  9-14 0.2 3  9-15 2 13  9-16 0.09 0.6  9-17 15 133  9-18 6 101  9-19 6 146  9-20 0.1 1  9-21 0.3 0.8  9-22 0.7 2  9-23 0.4 10  9-24 0.2 0.7  9-25 0.3 0.7  9-26 0.4 7  9-27 0.4 7  9-28 1 24  9-29 0.1 3  9-30 0.2 5  9-31 1 33  9-32 0.3 8  9-33 0.2 6  9-34 0.5 4  9-35 1 16  9-36 0.9 21  9-37 0.2 3  9-38 0.3 3  9-39 7 348  9-40 0.7 11  9-41 6 201 10-1  0.1 0.7 10-2  0.5 4 10-3  0.06 0.6 10-4  0.4 29 10-5  0.2 21 10-6  0.8 71 10-7  0.2 4 10-8  0.7 21 10-9  0.4 15 11-1  0.03 0.5 11-2  0.01 0.6 12-1  1 37 12-2  0.2 3 12-3  2 42 12-4  0.8 3 12-5  0.8 7 12-6  0.4 15 12-7  0.1 2 13-1  3 139 13-2  13 1009 13-3  8 466 13-4  4 183 13-5  15 903 13-6  26 179 13-7  8 210 13-8  9 176 13-9  10 186 13-10 6 178 13-11 5 126 13-12 1 16 14 10 38 15-1  148 1481 15-2  51 1104 15-3  341 1050 15-4  41 958 15-5  14 293 15-6  85 1481 15-7  127 1481 15-8  161 1481 15-9  644 1481 15-10 31 841 15-11 13 182 18 0.1 10 19 162 870 20 358 1481 21-1  6 46 21-2  3 11 21-3  79 234 21-4  29 243 21-5  46 314 21-6  3 55 21-7  11 135 21-8  89 1298 21-9  15 319 21-10 8 78 21-11 0.3 6 21-12 7 128 21-13 24 297 21-14 18 224 21-15 12 242 21-16 69 842 21-17 19 208 21-18 2 73 21-19 35 460 21-20 10 105 21-21 3 44 21-22 72 888 21-23 0.8 13 21-24 120 1053 21-25 83 747 21-26 0.7 11 21-27 36 809 21-28 39 453 21-29 21 400 22-1  30 447 22-2  0.2 5 22-3  1 57 22-4  74 1180 22-5  6 70 22-6  6 211 22-7  0.3 13 22-8  0.1 6 22-9  0.06 2 22-10 0.07 3 22-11 0.1 4 22-12 124 >1496 22-13 3 39 22-14 0.6 28 22-15 1 18 22-16 5 122 22-17 17 503 22-18 2 72 22-19 0.7 25 22-20 2 31 22-21 0.7 41 22-22 0.4 13 22-23 0.1 6 22-24 100 >1496 22-25 6 208 22-26 6 117 22-27 6 157 22-28 3 73 22-29 2 37 22-30 86 >1496 22-31 1 47 22-32 2 83 22-33 2 81 22-34 8 163 22-35 6 145 22-36 2 97 22-37 88 >1496 22-38 0.2 5 22-39 0.2 14 22-40 23 582 22-41 18 641 22-42 18 582 22-43 1 64 22-44 5 22 22-45 2 34 22-46 3 95 22-47 6 100 22-48 2 73 22-49 2 29 22-50 0.6 16 22-51 0.4 9 22-52 1 25 22-53 4 87 22-54 1 28 22-55 4 53 22-56 2 46 22-57 14 280 22-58 4 128 22-59 0.2 7 22-60 0.1 6 22-61 0.4 10 22-62 0.9 33 22-63 0.5 20 22-64 4 156 22-65 1 16 22-66 2 82 22-67 1 68 22-68 0.1 8 22-69 0.2 9 22-70 0.04 1 22-71 0.1 4 22-72 0.3 13 23 4 105 24-1  10 59 24-2  41 917 25 0.08 2 26 0.4 5 27-1  0.3 2 27-2  0.3 6 27-3  1 16 27-4  3 85 27-5  50 235 28 4 74 29 2 96 29-A  1 40 30-1  0.2 8 30-2  0.3 15 30-3  0.8 28 30-4  0.9 33 30-5  4 120 30-6  0.9 38 30-7  0.5 9 30-8  1 72 30-9  0.3 5 30-10 21 745 30-11 0.2 11 30-12 6 71 30-13 0.9 20 30-14 2 30 30-15 1 19 30-16 0.9 38 30-17 3 96 30-18 2 44 30-19 1 37 30-20 8 240 30-21 6 145 30-22 5 123 30-23 2 40 30-24 4 96 30-25 4 120 30-26 0.2 3 30-27 0.07 5 30-28 3 102 30-29 6 249 30-30 1 50 30-31 8 318 30-32 4 88 30-33 2 40 30-34 3 83 30-35 4 71 30-36 1 40 30-37 3 103 30-38 7 156 30-39 2 38 30-40 2 58 30-41 31 336 30-42 41 798 30-43 12 318 30-44 11 318 30-45 3 97 30-46 1 37 30-47 3 103 30-48 4 71 30-49 0.3 18 30-50 2 27 30-51 14 298 30-52 3 76 30-53 11 262 30-54 375 1481 30-55 74 491 30-56 18 373 30-57 14 466 30-58 76 809 30-59 15 336 30-60 39 484 30-61 37 603 30-62 5 102 30-63 11 258 30-64 188 1481 30-65 12 271 30-66 19 353 30-67 108 849 30-68 45 445 30-69 31 671 30-70 21 423 30-71 200 1481 30-72 72 1186 30-73 130 1481 30-74 6 132 30-75 22 221 30-76 74 285 30-77 0.2 9 30-78 0.3 12 31 0.4 8 32 94 510 33-1  2 26 33-2  2 64 34-1  1 16 34-2  5 93 34-3  13 91 34-4  12 70 34-5  13 318 34-6  5 107 34-7  6 94 34-8  14 191 34-9  18 372 34-10 20 318 34-11 12 283 34-12 15 195 34-13 2 44 34-14 0.3 8 34-15 5 194 34-16 2 35 34-17 10 158 34-18 8 137 34-19 11 184 34-20 13 115 34-21 4 63 34-22 6 176 34-23 14 230 34-24 7 84 34-25 28 350 34-26 10 238 34-27 32 448 34-28 92 1049 34-29 387 1481 34-30 35 363 34-31 61 704 34-32 6 166 34-33 153 711 34-34 60 830 34-35 44 248 34-36 42 298 34-37 138 570 34-38 59 542 34-39 0.9 42 34-40 0.1 2 34-41 3 48 34-42 3 96 34-43 11 234 34-44 2 63 34-45 1 46 34-46 2 139 34-47 2 79 34-48 0.3 13 34-49 0.2 9 34-50 0.2 8 34-51 4 37 34-52 4 154 34-53 0.3 15 34-54 0.6 44 34-55 1 28 34-56 2 40 34-57 0.1 9 34-58 0.5 22 34-59 0.2 3 34-60 8 115 34-61 2 38 34-62 1 47 35-1  0.1 5 35-2  0.2 10 35-3  3 35 36-1  5 77 36-2  0.6 10 37-1  2 13 37-2  0.4 3 37-3  1 12 37-4  0.6 2 37-5  0.7 6 37-6  0.3 1 37-7  2 9 37-8  15 35 37-9  0.8 3 37-10 0.7 3 37-11 0.6 2 37-12 3 9 37-13 3 8 37-14 5 24 37-15 0.4 3 37-16 79 366 37-17 95 247 37-18 159 585 37-19 138 463 37-20 105 521 38-1  3 68 38-2  20 628 38-3  10 185 38-4  12 191 38-5  4 214 38-6  2 69 38-7  5 80 38-8  14 428 38-9  38 558 38-10 5 158 38-11 4 78 38-12 128 1435 38-13 21 339 38-14 25 334 38-15 0.9 21 38-16 7 111 38-17 11 149 38-18 7 106 38-19 23 334 38-20 19 326 38-21 7 173 38-22 19 249 38-23 94 1194 38-24 5 179 38-25 18 168 38-26 2 69 38-27 11 162 38-28 6 79 38-29 185 1481 38-30 62 507 38-31 33 656 38-32 4 86 38-33 26 265 38-34 2 28 38-35 8 144 38-36 15 233 38-37 8 114 38-38 13 183 38-39 16 303 38-40 18 279 38-41 13 175 38-42 19 237 38-43 20 322 38-44 0.1 2 38-45 0.1 0.5 38-46 2 59 38-47 0.2 6 39-1  0.09 2 39-2  0.1 3 40-1  272 >1496 40-2  0.5 48  40-1A 6 39 40-3  119 >1496 40-4  102 1333 40-5  449 >1496 40-6  12 365 40-7  7 36 40-8  0.3 6 40-9  12 352 40-10 14 355 40-11 0.2 7 40-12 2 73 40-13 115 >1496 40-14 1 65 40-15 0.08 2 40-16 0.3 18 40-17 0.04 1 40-18 235 >1496 40-19 0.3 10 40-20 1 43 40-21 171 >1496 40-22 4 195 40-23 2 237 40-24 8 184 40-25 63 940 40-26 0.08 5 40-27 8 273 40-28 0.2 32 40-29 0.07 4 40-30 326 >1496 40-31 0.1 2 40-32 12 177 40-33 0.03 0.8 40-34 4 105 40-35 0.8 30 40-36 65 >1496 40-37 16 506 40-38 1 103 40-39 30 760 40-40 0.2 9 40-41 584 >1496 40-42 64 775 40-43 0.3 14 40-44 0.1 0.8 40-45 38 770 40-46 1 60 40-47 215 >1496 40-48 0.4 6 40-49 5 137 40-50 0.1 6 40-51 598 >1496 40-52 0.6 20 40-53 400 >1496 40-54 0.9 24 40-55 13 409 40-56 3 159 40-57 415 >1496 40-58 0.2 7 40-59 0.5 3 40-60 45 758 40-61 0.06 3 40-62 38 832 40-63 0.03 1 40-64 0.05 2 40-65 2 129 40-66 344 >1496 40-67 37 773 40-68 69 981 40-69 9 667 40-70 0.2 9 40-71 24 814 40-72 1 37 40-73 139 >1496 40-74 1 35 40-75 0.2 7 40-76 13 225 40-77 0.7 13 40-78 12 264 40-79 8 133 40-80 14 325 40-81 0.1 5 40-82 26 444 40-84 0.04 3 40-85 0.02 0.2 40-86 0.06 0.6 40-87 13 524 40-88 200 >1496 40-89 13 466 40-90 9 84 40-91 67 323 40-92 0.04 0.2 40-93 166 >1496 40-94 234 >1496 40-95 28 794 40-96 0.09 2 40-97 25 1037 40-98 1 31 40-99 506 >1496  40-100 18 216  40-101 18 276  40-102 0.05 1  40-103 0.1 3  40-104 0.2 11  40-105 0.08 1  40-106 4 31  40-108 0.09 2  40-109 0.05 0.8  40-110 2 64 41-1  8 218  41-1A 106 >1496  41-1B 4 161 41-2  86 >1496 41-3  1 33 41-4  0.09 2 41-5  10 595 41-6  23 851 41-7  12 468 41-8  0.8 153 41-9  15 440 41-10 0.03 2 41-11 0.08 2 41-12 0.2 9 41-13 86 1004 41-14 45 1419 41-15 0.1 2 41-16 24 912 41-17 46 1392 41-18 0.1 10 41-19 0.3 9 41-20 0.6 17 41-21 11 308 41-22 28 1053 41-23 46 1430 41-24 26 1029 41-25 27 1078 41-26 16 759 41-27 307 >1496 41-28 20 735 42 8 336 43-1  4 13 43-2  18 67 43-3  0.9 5 43-4  0.05 0.1 44-1  155 1481 44-2  16 195 45-1  7 301 45-2  378 1481 46 0.03 0.1 47-3  2 32 47-4  2 83 48-1  1 24 48-2  113 487 49-1  0.6 20 49-2  0.4 22 50-1  1 47 50-2  2 62 

What is claimed is:
 1. A compound of formula I or a pharmaceutically acceptable salt, or a stereoisomer thereof:

R^(a) and R⁴ are each independently selected from hydrogen and C₁₋₄alkyl; A is selected from aryl, and heteroaryl; n is independently 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; X is independently selected from C, N, O and S; R³ and R⁷ are each independently selected from hydrogen, halogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ heteroalkyl, aryl C₀₋₁₀ alkylC₀₋₁₀ alkyl, C₃₋₈ cycloalkylC₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl, (C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl, and wherein each of R³ and R⁷ are independently substituted with 0, 1, 2, 3, or 4 R^(5a) substituents; R^(5a) is selected from: halogen, C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₂₋₁₀ alkynyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, (C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, C₂₋₁₀ alkenyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl (carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, (C₃₋₈)cycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, heteroarylC₀₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, (C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, ((C₀₋₁₀)alkyl)₁₋₂aminocarbonyloxy, (C₀₋₁₀)heteroalkylaminocarbonyloxy, aryl (C₀₋₁₀)alkylaminocarbonyloxy, (C₃₋₈)cycloalkyl(C₀₋₁₀)alkylaminocarbonyloxy, heteroaryl(C₀₋₁₀)alkylaminocarbonyloxy, (C₃₋₈)heterocycloalkyl(C₀₋₁₀)alkylaminocarbonyloxy, C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, (C₀₋₁₀)heteroalkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, aryl C₀₋₁₀alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, heteroarylC₀₋₁ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, (C₃₋₈)heterocycloalkylC₀₋₁₀alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl (oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl (oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl, (C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl, —CO₂(C₀₋₁₀ alkyl), —(C₀₋₁₀ alkyl)CO₂H, Oxo (═O); C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, (C₃₋₈) cycloalkylsulfonyl, (C₃₋₈) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, —SO₂N(C₁₋₆alkyl)₁₋₂, —SO₂C₁₋₆alkyl, —SO₂CF₃, —SO₂CF₂H, C₁₋₁₀ alkylsulfinyl, —Si(CH₃)₃, amino, (C₀₋₁₀ alkyl)₁₋₂ amino, C₁₋₄acylamino C₀₋₁₀ alkyl, hydroxy, (C₁₋₁₀ alkyl)OH, C₀₋₁₀ alkylalkoxy, cyano, (C₁₋₆alkyl)cyano, and C₁₋₆haloalkyl; wherein two R^(5a) and the atom to which they are attached may optionally form a −4, −5, or −6 member saturated ring system; wherein R^(5a) is each optionally substituted with 1, 2, 3, or 4 R⁶ substituents, and R⁶ is independently selected from: halogen, C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₂₋₁₀ alkynyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, (C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, C₂₋₁₀ alkenyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl (carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, (C₃₋₈)cycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, heteroarylC₀₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, (C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, ((C₀₋₁₀)alkyl)₁₋₂aminocarbonyloxy, aryl (C₀₋₁₀)alkylaminocarbonyloxy, (C₃₋₈)cycloalkyl(C₀₋₁₀)alkylaminocarbonyloxy, heteroaryl(C₀₋₁₀)alkylaminocarbonyloxy, (C₃₋₈)heterocycloalkyl(C₀₋₁₀)alkylaminocarbonyloxy, C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, aryl C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, (C₃₋₈)heterocycloalkyl C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, C₁₋₁₀ alkyl (oxy)₀₋₁carbonylaminoC₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl (oxy)₀₋₁carbonylaminoC₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁carbonylaminoC₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁carbonylaminoC₀₋₁₀ alkyl, (C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁carbonylaminoC₀₋₁₀ alkyl, —CO₂(C₀₋₁₀ alkyl), —(C₀₋₁₀ alkyl)CO₂H, Oxo (═O), C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, (C₃₋₈) cycloalkylsulfonyl, (C₃₋₈) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, —SO₂N(C₁₋₆alkyl)₁₋₂, —SO₂C₁₋₆alkyl, —SO₂CF₃, —SO₂CF₂H, C₁₋₁₀ alkylsulfinyl, —OSi(C₁₋₁₀alkyl)₃, —Si(CH₃)₃, amino, (C₀₋₁₀ alkyl)₁₋₂ amino, -(oxy)₀₋₁(carbonyl)₀₋₁N(C₀₋₁₀ alkyl)₁₋₂ C₁₋₄acylamino C₀₋₁₀ alkyl, hydroxy, (C₁₋₁₀ alkyl)OH, C₁₋₁₀ alkoxy, (C₁₋₁₀ alkyl)cyano, cyano, and C₁₋₆haloalkyl; and wherein two R⁶ and the atoms to which they are attached may optionally form a 3-, 4-, 5-, or 6-membered saturated ring system; and R⁶ is optionally substituted with 1, 2, or 3 substituents selected from hydrogen, hydroxy, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₁₋₁₀ alkyl)OH, halogen, CO₂H, —(C₀₋₆)alkylCN, —O(C═O)C₁-C₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy, trifluoromethyl, trifluoroethyl, —N—C(O)O(C₀₋₆)alkyl, C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, oxo (O═), (C₃₋₈) cycloalkylsulfonyl, (C₃₋₈) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, —SO₂N(C₁₋₆alkyl)₁₋₂, —SO₂C₁₋₆alkyl, —SO₂CF₃, —Si(CH₃)₃, —SO₂CF₂H, —C₁₋₁₀ alkylsulfinyl, —OSi(C₁₋₁₀alkyl)₃, —O₍₀₋₁₎(C₁₋₁₀)haloalkyl, amino(C₁₋₆alkyl)₀₋₂ and NH₂; with the proviso that the compound of formula I is other than: 1-[3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl]-3-({4-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; and 1-[3-(cyanomethyl)-1-(naphthalene-2-ylsulfonyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide.
 2. A compound or a pharmaceutically acceptable salt, or a stereoisomer thereof according to claim 1 selected from: tert-Butyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{3-[(4-bromophenyl)amino]-4-carbamoyl-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; tert-butyl 4-(3-{[3-(1H-benzotriazol-1-ylmethyl)phenyl]amino}-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 3-(4-carbamoyl-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate; tert-butyl 4-[4-carbamoyl-3-({4-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenyl}amino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-[4-carbamoyl-3-(pyridin-4-ylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 3-[4-carbamoyl-3-({4-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenyl}amino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; tert-Butyl-4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)-3-methylpiperidine-1-carboxylate; 1-[3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)cyclohexyl]-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)cyclohexyl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; tert-butyl 3-(4-carbamoyl-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazol-1-yl)-3-(cyanomethyl)pyrrolidine-1-carboxylate; tert-butyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)pyrrolidine-1-carboxylate; tert-butyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)cyclohexanecarboxylate; tert-butyl {4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)cyclohexyl}carbamate; 1-[3-(cyanomethyl)oxetan-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-(3-cyano-1-(cyanomethyl)cyclobutyl)-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-(3-cyano-1-(cyanomethyl)cyclobutyl)-3-((4-(methylsulfonyl)phenyl)amino)-1H-pyrazole-4-carboxamide; tert-butyl 6-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-6-(cyanomethyl)-2-azaspiro[3.3]heptane-2-carboxylate; 1-[4-(Cyanomethyl)-1-(3,4-dimethoxyphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-isoquinolin-4-ylpiperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-quinolin-4-ylpiperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2-methylpyridin-4-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(5-fluoropyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2-methoxypyridin-4-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[5-(trifluoromethyl)pyridin-3-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[6-(2-hydroxyethoxy)pyridin-2-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(4-fluoro-3-methoxyphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3-fluoro-5-methoxyphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[6-(difluoromethoxy)pyridin-3-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(5,6-dimethylpyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[6-(1-methylethoxy)pyridin-2-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(6-ethoxypyridin-2-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3-cyclopropylphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(6-cyanopyridin-2-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[5-(difluoromethoxy)pyridin-2-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(6-methylpyridin-2-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(5-cyanopyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(6-fluoropyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3-methoxypyridin-2-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-pyrimidin-5-ylpiperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2-methoxypyrimidin-5-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(4-cyanophenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3-fluorophenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[6-(trifluoromethyl)pyridin-3-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2-methylpyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-pyridin-3-ylpiperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(4-methylpyridin-2-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(5-fluoro-2-methylphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(4-methylpyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3-fluoro-4-methylphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; methyl 6-[4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidin-1-yl]pyridine-2-carboxylate; 1-[4-(cyanomethyl)-1-(6-ethoxypyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(5-methoxypyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(4-fluorophenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(4-methylphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3,5-difluorophenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2-methoxyphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(4-fluoro-3-methylphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2-fluoro-3-methylphenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(4-fluoropyridin-2-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3,4-difluorophenyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-pyridin-4-ylpiperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(4-methylpyrimidin-5-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(5-methylpyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[6-(fluoromethyl)pyridin-2-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2-fluoropyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(6-methylpyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(6-methoxypyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(6-fluoropyridin-2-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[4-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(6-fluoro-5-methylpyridin-3-yl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; tert-Butyl 4-(4-carbamoyl-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-[4-carbamoyl-3-({4-[(1-methylethoxy)carbonyl]phenyl}amino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-{[3-(1H-imidazol-1-ylmethyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2,2,2-trifluoroethyl 4-(3-{[3-(1H-benzotriazol-1-ylmethyl)phenyl]amino}-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 1-[4-(cyanomethyl)tetrahydro-2H-pyran-4-yl]-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carboxamide; tert-butyl 4-{4-carbamoyl-3-[(2-cyanopyrimidin-5-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-Butyl 4-(4-carbamoyl-3-((4-fluorophenyl)amino)-1H-pyrazol-1-yl)-4-(1-cyanoethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-[cyano(cyclopropyl)methyl]piperidine-1-carboxylate; tert-butyl-4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate; 1-[4-(cyanomethyl)tetrahydro-2H-pyran-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[8-(cyanomethyl)-1,4-dioxaspiro[4.5]dec-8-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[8-(cyanomethyl)-1,4-dioxaspiro[4.5]dec-8-yl]-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carboxamide; 1-(4-(Cyanomethyl)tetrahydro-2H-thiopyran-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide; 1-(4-(Cyanomethyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide; tert-Butyl 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-{[4-(methoxycarbonyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-Butyl 4-[4-(aminocarbonyl)-3-({4-[(methylamino)carbonyl]phenyl}amino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(4-cyanophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-(6-(2-hydroxypropan-2-yl)pyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-(6-(1-hydroxyethyl)pyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-(4-(2-hydroxypropan-2-yl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-(4-(1-hydroxyethyl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(3-(4-acetylphenylamino)-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-{[4-(trifluoroacetyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(6-cyanopyridin-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-{[4-(1-methyl-1H-pyrazol-3-yl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{3-[(2-aminopyridin-4-yl)amino]-4-carbamoyl-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-[4-carbamoyl-3-({4-[(trifluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-[4-carbamoyl-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(2-methylpyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-{[2-(hydroxymethyl)pyridin-4-yl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(2-methoxypyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(4-sulfamoylphenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-{[4-(dimethylsulfamoyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-{[4-(dimethylcarbamoyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-{[3-fluoro-4-(morpholin-4-ylcarbonyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-{[4-(morpholin-4-ylcarbonyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(4-cyano-3-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(2-carbamoylpyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(3,4-difluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(2-chloropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-{[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(2,6-dichloropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(2-cyanopyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-[4-carbamoyl-3-(pyridin-3-ylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(5-fluoropyridin-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(5-chloropyridin-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; 2,2-difluoroethyl 4-(4-carbamoyl-3-{[6-(cyclobutyloxy)pyridin-3-yl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2,2-difluoroethyl 4-{4-carbamoyl-3-[(6-cyclobutylpyridin-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; 2,2-difluoroethyl 4-{4-carbamoyl-3-[(2-methoxypyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; 2,2-difluoroethyl 4-{4-carbamoyl-3-[(6-cyclopropylpyridin-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; 2,2-difluoroethyl 4-{4-carbamoyl-3-[(2-cyclopropylpyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; 2,2,2-Trifluoroethyl 4-(4-carbamoyl-3-(6-(2-hydroxypropan-2-yl)pyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2,2,2-trifluoroethyl 4-(4-carbamoyl-3-(4-(trifluoromethylsulfonyl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2,2,2-trifluoroethyl 4-(4-carbamoyl-3-(6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2,2,2-trifluoroethyl 4-(3-(3-(1H-pyrazol-3-yl)phenylamino)-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2,2,2-trifluoroethyl 4-(4-carbamoyl-3-(3-(1-methyl-1H-pyrazol-4-yl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2,2,2-trifluoroethyl 4-(4-carbamoyl-3-(5-(1-methyl-1H-pyrazol-4-yl)pyridinl-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2,2,2-trifluoroethyl 4-(4-carbamoyl-3-(pyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2,2,2-trifluoroethyl 4-(4-carbamoyl-3-(5-fluoropyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2,2,2-trifluoroethyl 4-{4-carbamoyl-3-[(5-chloropyridin-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; 2,2,2-Trifluoroethyl 4-(4-carbamoyl-3-{[6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2,2,2-trifluoroethyl 4-(4-carbamoyl-3-{[6-(1H-pyrazol-4-yl)pyridin-3-yl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-Butyl 4-{3-[(3-bromophenyl)amino]-4-carbamoyl-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-{[4-(2-methoxy-2-oxoethyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(3,5-difluorophenyl)amino]-H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-{[6-(morpholin-4-yl)aphthal-3-yl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate tert-butyl 4-{4-carbamoyl-3-[(6-fluoropyridin-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-[4-carbamoyl-3-(pyridazin-4-ylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-Butyl 4-(4-carbamoyl-3-(pyrimidin-4-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-(6-methylpyridin-2-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-(pyridin-2-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-(5-fluoropyridin-2-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-(4-fluoropyridin-2-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-(pyridazin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-(pyrazine-2-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-(6-methylpyrazine-2-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-(6-methoxypyridin-2-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-(2,6-dimethylpyrimidin-4-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-(6-methylpyrimidin-4-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(4-carbamoyl-3-((5-fluoropyridin-3-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-Butyl 4-(4-carbamoyl-3-{[4-(3,5-dimethylisoxazol-4-yl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-Butyl 4-{4-carbamoyl-3-[(4′-chlorobiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(4′-fluorobiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-[3-(biphenyl-3-ylamino)-4-carbamoyl-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(4′-methoxybiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(4′-hydroxybiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(4′-methylbiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(2′-methylbiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(3′-chlorobiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(3-naphthalen-2-ylphenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(2′-fluorobiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-{4-carbamoyl-3-[(2′-hydroxybiphenyl-3-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; [4-({1-[1-(tert-Butoxycarbonyl)-4-(cyanomethyl)piperidin-4-yl]-4-carbamoyl-1H-pyrazol-3-yl}amino)phenyl]acetic acid; 1-[3-(Cyanomethyl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[3-(Cyanomethyl)-1-methylazetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[1-(Biphenyl-4-ylmethyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(pyridin-3-ylmethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[1-(3-cyanobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[1-(4-cyanobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3-cyanopropyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[1-(2-chlorobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(4-methylbenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(naphthalene-1-ylmethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(cyclohexylmethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[1-(1,3-benzodioxol-5-ylmethyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3-hydroxybenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{1-[4-(acetylamino)benzyl]-4-(cyanomethyl)piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(6-methoxynaphthalen-2-yl)methyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2,6-dichlorobenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[3-(methylsulfanyl)propyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2-ethoxybenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(2E)-3-phenylprop-2-en-1-yl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3-fluorobenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[4-(trifluoromethyl)benzyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[1-(1-benzofuran-2-ylmethyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[1-(4-chloro-2-fluorobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(4-propylbenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2,6-difluorobenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[4-(1-methylethyl)benzyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3-phenylprop-2-yn-1-yl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2,3,6-trifluorobenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[4-(1-methylethoxy)benzyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3,4-dimethylbenzyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; methyl 2-({4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidin-1-yl}methyl)benzoate; 1-(4-(Cyanomethyl)-1-((1-ethyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(pyridin-3-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(cyclohexylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(4-methyl-1H-imidazol-2-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1H-pyrazol-4-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(cyclohexylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-benzyl-4-(cyanomethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-benzyl-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2-fluorobenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3-fluorobenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(4-fluorobenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1H-pyrazol-5-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(pyrazin-2-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(2-methyl-1,3-thiazol-5-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(pyrazolo[1,5-a]pyridin-3-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(furan-2-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1H-indol-5-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1H-indol-7-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(2-fluoro-5-methylpyridin-3-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(2-fluoropyridin-3-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-{[3-(1-hydroxy-1-methylethyl)cyclobutyl]methyl}piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1,3-oxazol-4-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(5-methylisoxazol-3-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1,3-oxazol-2-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(1-methyl-1H-pyrazol-5-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(1-methyl-1H-pyrazol-3-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(isoxazol-3-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(6-fluoropyridin-2-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(pyrazolo[1,5-a]pyridin-7-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(pyrazolo[1,5-a]pyridin-2-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(pyridazin-3-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(5-fluoropyridin-2-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(3-methoxycyclobutyl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(5-fluoropyridin-3-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1H-indol-2-ylmethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(1H-benzimidazol-2-ylmethyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1H-indol-2-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(2-fluoro-5-methylpyridin-3-yl)methyl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(isoxazol-3-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(6-fluoropyridin-2-yl)methyl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(pyridazin-3-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(5-fluoropyridin-2-yl)methyl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(5-fluoropyridin-3-yl)methyl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(4-fluoropyridin-2-yl)methyl]piperidin-4-yl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(pyridin-3-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(pyrazin-2-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(furan-2-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1H-indol-5-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1H-indol-6-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1H-indol-4-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1H-indol-7-ylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(2-chlorobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(4-hydroxybenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(3-chlorobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(3-cyanobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3-methoxybenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2-phenylethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(4-methoxybenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2-methoxybenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(6-oxo-1,6-dihydropyridin-2-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(6-hydroxypyridin-3-yl)methyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(4-cyanobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3-hydroxybenzyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(4-chlorobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(2-cyanobenzyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-(4-(Cyanomethyl)-1-(1-phenylethyl)piperidin-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide; 1-(4-(Cyanomethyl)-1-(2-fluoroethyl)piperidin-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(cyclopropylmethyl)piperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-(4-(Cyanomethyl)-1-(pyridin-2-yl)piperidin-4-yl)-3-(4-fluorophenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(Cyanomethyl)-1-pyrimidin-4-ylpiperidin-4-yl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; Methyl 4-(4-carbamoyl-3-(4-(trifluoromethylsulfonyl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2-methoxyethyl 4-(4-carbamoyl-3-(4-(trifluoromethylsulfonyl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; methyl 4-(4-carbamoyl-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; benzyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; methyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; 2-Methoxy-1,1-dimethylethyl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; 1-Hydroxy-2-methylpropan-2-yl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; 2,2,2-Trifluoroethyl 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; 2,2,2-trifluoroethyl 4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 1,1,1-trifluoropropan-2-yl 4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; cyclobutyl 4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; cyclobutylmethyl 4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; (2,2-difluorocyclopropyl)methyl 4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2,2-difluoroethyl 4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; (1-methylcyclopropyl)methyl 4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 1,3-difluoropropan-2-yl 4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; (trimethylsilyl)methyl 4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2,2-difluoro-3-hydroxypropyl 4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 1-cyclopropylethyl 4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; (1-hydroxycyclopropyl)methyl 4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 1,1,1-trifluoropropan-2-yl 4-(4-carbamoyl-3-(4-fluorophenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2,2-difluoroethyl 4-(4-carbamoyl-3-(5-fluoropyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tetrahydrofuran-3-yl 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tetrahydro-2H-pyran-4-yl 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; oxetan-3-yl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; cyclopropylmethyl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; (3-methyloxetan-3-yl)methyl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tetrahydro-2H-pyran-4-ylmethyl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tetrahydrofuran-3-ylmethyl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; 1-methoxypropan-2-yl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; 2-methoxypropyl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tetrahydro-2H-pyran-3-yl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; oxetan-3-yl 4-(4-carbamoyl-3-(4-(trifluoromethylsulfonyl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2,2-difluoroethyl 4-(4-carbamoyl-3-(2-fluoropyridin-4-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2-methylpropyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; 2,2-dimethylpropyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; cyclopentyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; cyclohexyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; 3-fluorobenzyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; 2-fluorobenzyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; 2,3-dihydro-1H-inden-2-yl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; 2-methoxyethyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; 4-carbamoyl-1-[4-(cyanomethyl)-1-{[tetrahydrofuran-3-yloxy]carbonyl}piperidin-4-yl]-3-(phenylamino)-1H-pyrazol-2-ium; tetrahydro-2H-pyran-4-yl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; pyridin-3-ylmethyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; pyridin-3-ylmethyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; pyridin-4-ylmethyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; 2-morpholin-4-ylethyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; 1-methylpiperidin-4-yl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; 2-(4-methylpiperazin-1-yl)ethyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; (1-methylpiperidin-4-yl)methyl 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate; 3,3,3-Trifluoropropyl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tetrahydrofuran-3-yl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tetrahydro-2H-pyran-4-yl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; 2-methoxyethyl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; Cyclopropylmethyl 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; 2-fluoroethyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; 2-methylpropyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; cyclopentyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; benzyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; 2-naphthalen-1-ylethyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; 2-morpholin-4-ylethyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; 2,2-dimethylpropyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; cyclohexyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; 2-phenylethyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; 2-methoxyethyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; 2-ethoxy-2-oxoethyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; 3-methoxypropyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; tetrahydrofuran-3-yl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; tetrahydro-2H-pyran-4-yl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; 2-(2-oxopyrrolidin-1-yl)ethyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; pyridin-3-ylmethyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; pyridin-4-ylmethyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; 2-pyridin-2-ylethyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; 3-pyridin-3-ylpropyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; 2-methoxybenzyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; 3-methoxybenzyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; 3-(dimethylamino)propyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; 2-(4-methylpiperazin-1-yl)ethyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; (1-methylpiperidin-4-yl)methyl 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate; cyclopentyl 3-(4-carbamoyl-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate; tetrahydrofuran-3-yl 3-(4-carbamoyl-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate; tetrahydro-2H-pyran-4-yl 3-(4-carbamoyl-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate; 1-cyclopropylethyl 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; 2-Hydroxy-1-methylethyl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; 1-[1-Acetyl-3-(cyanomethyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(Cyanomethyl)-1-propanoylpiperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{1-[(2E)-but-2-enoyl]-4-(cyanomethyl)piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(Cyanomethyl)-1-(cyclopropylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(methoxyacetyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-pentanoylpiperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(N,N-dimethylglycyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(phenylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(pyridin-3-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(pyridin-2-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(pyridin-4-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(pyrazin-2-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(cyclohexylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(thiophen-2-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(2-oxopyrrolidin-1-yl)acetyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(thiophen-3-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(2E)-3-pyridin-3-ylprop-2-enoyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(4-methoxyphenyl)carbonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{1-[(4-chlorophenyl)carbonyl]-4-(cyanomethyl)piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{1-[(2-chlorophenyl)carbonyl]-4-(cyanomethyl)piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{1-[(3-chlorophenyl)carbonyl]-4-(cyanomethyl)piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1H-indol-2-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-{[4-(dimethylamino)phenyl]carbonyl}piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(4-methoxyphenyl)acetyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(naphthalene-1-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(1-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(3,4-dimethoxyphenyl)carbonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(3-morpholin-4-ylphenyl)carbonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[1-(biphenyl-2-ylcarbonyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-{[4-(trifluoromethyl)phenyl]acetyl}piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(4-morpholin-4-ylphenyl)carbonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(quinolin-2-ylcarbonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(diphenylacetyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-{[4-(4-methylpiperazin-1-yl)phenyl]carbonyl}piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(hydroxyacetyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[3-(cyanomethyl)-1-propanoylazetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[3-(cyanomethyl)-1-(2,2-dimethylpropanoyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[3-(cyanomethyl)-1-(pyridin-2-ylcarbonyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(tetrahydrofuran-2-ylacetyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2,2-difluoropropanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[3-fluoro-2-(fluoromethyl)-2-methylpropanoyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(methoxyacetyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(cyclopropylacetyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(2R)-2-hydroxy-3-methylbutanoyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(2S)-2-hydroxy-3-methylbutanoyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3,3,3-trifluoro-2-methylpropanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanoacetyl)-4-(cyanomethyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3-hydroxy-3-methylbutanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-{[1-(trifluoromethyl)cyclobutyl]carbonyl}piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(1H-imidazol-1-ylacetyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(3,3-difluorocyclobutyl)carbonyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3,3-dimethylbutanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3,3,3-trifluoro-2,2-dimethylpropanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-{[1-(trifluoromethyl)cyclopropyl]carbonyl}piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(methylsulfonyl)acetyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(2,2-difluorobutanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(1-methylcyclobutyl)carbonyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(3,3-difluoro-2-hydroxy-2-methylpropanoyl)piperidin-4-yl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(3R)-3-hydroxybutanoyl]piperidin-4-yl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-(4-(Cyanomethyl)-1-(3,3,3-trifluoropropanoyl)piperidin-4-yl)-3-(4-fluorophenylamino)-1H-pyrazole-4-carboxamide; 1-(4-(cyanomethyl)-1-(3,3,3-trifluoropropanoyl)piperidin-4-yl)-3-(2-fluoropyridin-4-ylamino)-1H-pyrazole-4-carboxamide; 1-(4-(cyanomethyl)-1-(3,3,3-trifluoropropanoyl)piperidin-4-yl)-3-(5-fluoropyridin-3-ylamino)-1H-pyrazole-4-carboxamide; 1-[1-(Cyanoacetyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[1-(cyanoacetyl)-4-(cyanomethyl)piperidin-4-yl]-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carboxamide; 1-[4-(Cyanomethyl)-1-(isopropylsulfonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(methylsulfonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(ethylsulfonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(furan-2-ylsulfonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(trifluoromethyl)sulfonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(phenylsulfonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[1-(benzylsulfonyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(4-methoxyphenyl)sulfonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{4-(cyanomethyl)-1-[(3-methoxyphenyl)sulfonyl]piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{1-[(3-chlorophenyl)sulfonyl]-4-(cyanomethyl)piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{1-[(2-chlorophenyl)sulfonyl]-4-(cyanomethyl)piperidin-4-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide 1-[4-(cyanomethyl)-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[1-(biphenyl-4-ylsulfonyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[4-(cyanomethyl)-1-(cyclopropylsulfonyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[3-(cyanomethyl)-1-(methylsulfonyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[3-(cyanomethyl)-1-(furan-2-ylsulfonyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(trifluoromethyl)sulfonyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[3-(cyanomethyl)-1-(phenylsulfonyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[1-(benzylsulfonyl)-3-(cyanomethyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(Cyanomethyl)-1-[(3-fluorophenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[3-(cyanomethyl)-1-(cyclohexylcarbamoyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(1-methylethyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(3,4-dimethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[1-(butylcarbamoyl)-3-(cyanomethyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(4-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[3-(cyanomethyl)-1-{[4-(1-methylethyl)phenyl]carbamoyl}azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[3-(cyanomethyl)-1-{[2-(1-methylethyl)phenyl]carbamoyl}azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; ethyl N-({3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidin-1-yl}carbonyl)alaninate; 1-{3-(cyanomethyl)-1-[(2,5-difluorophenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(3-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(2,4,6-trimethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{1-[(3-chloro-4-methylphenyl)carbamoyl]-3-(cyanomethyl)azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{1-[(4-chloro-2-methylphenyl)carbamoyl]-3-(cyanomethyl)azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(4-cyanophenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(2,5-dimethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{1-[(5-chloro-2-methylphenyl)carbamoyl]-3-(cyanomethyl)azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[3-(cyanomethyl)-1-(propylcarbamoyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(2,4-dimethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(3,5-dimethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(3,4-difluorophenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{1-[(3-chloro-2-methylphenyl)carbamoyl]-3-(cyanomethyl)azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(2-ethyl-6-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{1-[(2-chloro-6-methylphenyl)carbamoyl]-3-(cyanomethyl)azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(2-methoxy-5-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(4-ethoxyphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(2-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(2,4-difluorophenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(1,1,3,3-tetramethylbutyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(2-ethoxyphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(2,6-dimethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{1-[(3-acetylphenyl)carbamoyl]-3-(cyanomethyl)azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-[3-(cyanomethyl)-1-{[(1R)-1-phenylethyl]carbamoyl}azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(4-ethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(3-ethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(4-methoxy-2-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(3-fluoro-4-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(5-fluoro-2-methylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(2-ethylphenyl)carbamoyl]azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{1-[(3-chloro-4-fluorophenyl)carbamoyl]-3-(cyanomethyl)azetidin-3-yl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(4-methylphenyl)carbamoyl]azetidin-3-yl}-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carboxamide; 1-{3-(cyanomethyl)-1-[(2,5-difluorophenyl)carbamoyl]azetidin-3-yl}-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carboxamide; 1-[1-(butylcarbamoyl)-3-(cyanomethyl)azetidin-3-yl]-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carboxamide; 4-(4-carbamoyl-3-(4-(trifluoromethylsulfonyl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-N-isopropylpiperidine-1-carboxamide; 4-(4-carbamoyl-3-(4-(trifluoromethylsulfonyl)phenylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-N-(4-cyanophenyl)piperidine-1-carboxamide; 4-[4-Carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)-N-(1-methylethyl)piperidine-1-carboxamide; 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)-N-(4-cyanophenyl)piperidine-1-carboxamide; 3-((4-chlorophenyl)amino)-1-(1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl]-3-{[4-(trifluoromethyl)phenyl]amino}-1H-pyrazole-4-carboxamide; 1-(1-(cyanomethyl)-4-(cyclohexylamino)cyclohexyl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(3-fluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(pyridin-2-ylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(pyridin-3-ylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(4-hydroxyphenyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(pyridin-3-ylamino)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(pyridin-3-ylamino)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,5-difluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(2-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(pyridin-2-ylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(4-hydroxypiperidin-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(3-hydroxyphenyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[methyl(phenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(3-fluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2-fluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(4-fluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(4-fluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(3,4-difluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(2,3-dihydro-1H-indol-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(pyridin-2-ylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(cyclohexylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2-fluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(2-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(4-hydroxypiperidin-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(cyclohexylamino)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-{4-[(3-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(2,3-dihydro-1H-indol-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(4,4-difluoropiperidin-1-yl)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2-hydroxyphenyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,4-difluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[methyl(phenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(3,4-difluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(3,4-difluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,4-difluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(pyridin-3-ylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(4-fluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(4-hydroxypiperidin-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(4,4-difluoropiperidin-1-yl)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(4-hydroxypiperidin-1-yl)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(3-hydroxyphenyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-{4-[(4-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(3-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(4-furphenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2-hydroxyphenyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(2,3-dihydro-1H-indol-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,5-difluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(cyclohexylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(4-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(4-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(2,3-dihydro-1H-indol-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(3-fluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(4-hydroxypiperidin-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(cyclohexylamino)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2-fluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(4-hydroxyphenyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2-fluorophenyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(4-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(3-chlorophenyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,5-difluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(3-fluorophenyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(4-hydroxypiperidin-1-yl)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2-hydroxyethyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(cyclopropylmethyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(4,4-difluoropiperidin-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2-methoxyethyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-{methyl[2-(methylsulfonyl)ethyl]amino}cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-{[4-(trifluoromethyl)phenyl]amino}cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(3-methoxyazetidin-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(pyridin-3-ylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(4-acetylpiperazin-1-yl)-1-(cyanomethyl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,2-difluoroethyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(methylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2-fluoroethyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[4-azetidin-1-yl-1-(cyanomethyl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(3-methoxyazetidin-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(phenylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,2-difluoroethyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(phenylamino)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,2-difluoroethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(phenylamino)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(1,3-dihydro-2H-isoindol-2-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-[4-(benzylamino)-1-(cyanomethyl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(3-methoxyazetidin-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(phenylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(4-cyanobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,2-difluoroethyl)amino]cyclohexyl}-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl}-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(phenylamino)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(phenylamino)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,2-difluoroethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-[cis-4-(benzylamino)-1-(cyanomethyl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-(1-(cyanomethyl)-4-((2,4-difluorobenzyl)amino)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide; 1-[4-amino-1-(cyanomethyl)cyclohexyl]-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,4-difluorobenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(3-hydroxybenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(4-cyanobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2-hydroxybenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(cyclohexylmethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(4-chlorobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(2-chlorobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2-fluorobenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(4-fluorobenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(pyridin-4-ylmethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(3-cyanobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(4-chlorobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(2-chlorobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(pyridin-2-ylmethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(benzylamino)-1-(cyanomethyl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(3-fluorobenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(3-chlorobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2-fluorobenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(pyridin-3-ylmethyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(3-chlorobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(3-fluorobenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(4-fluorobenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(4-hydroxybenzyl)amino]cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-{4-[(2-cyanobenzyl)amino]-1-(cyanomethyl)cyclohexyl}-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-[4-(benzylamino)-1-(cyanomethyl)cyclohexyl]-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazole-4-carboxamide; 1-(1-(Cyanomethyl)-4-(3-fluorophenylsulfonamido)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide; 1-(4-(Cyanomethyl)-1-(2,2-difluoropropanoyl)-3-fluoropiperidin-4-yl)-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazole-4-carboxamide; 1-(4-(cyanomethyl)-1-(2,2-difluoropropanoyl)-3-fluoropiperidin-4-yl)-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazole-4-carboxamide; 1-(4-(cyanomethyl)-1-(2,2-difluoropropanoyl)-3-fluoropiperidin-4-yl)-3-((6-fluoropyridin-3-yl)amino)-1H-pyrazole-4-carboxamide; 1-[1-(cyanomethyl)-4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)cyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide; 1-{1-(cyanomethyl)-4-[(2,2,2-trifluoroethyl)carbamoyl]cyclohexyl}-3-(phenylamino)-1H-pyrazole-4-carboxamide; 2,2-Difluoroethyl 4-(4-carbamoyl-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate; 1-(4-amino-1-(cyanomethyl)cyclohexyl)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazole-4-carboxamide; 4-amino-1-(cyanomethyl)cyclohexyl)-3-((4-((difluoromethyl)sulfonyl)phenyl)amino)-1H-pyrazole-4-carboxamide; tert-butyl-4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate; tert-butyl-4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)-3-methylpiperidine-1-carboxylate; tetrahydrofuran-3-yl 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; and tetrahydrofuran-3-yl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate.
 3. A compound according to claim 1, wherein R^(a) is hydrogen or methyl.
 4. A compound according to claim 3, wherein R⁴ is hydrogen or methyl.
 5. A compound according to claim 4, wherein A is selected from: furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, naphthyridinyl, benzothienyl, benzofuranyl, benzimidazole, benzpyrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolizinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, benzisoxazolyl, 5,6,7,8-tetrahydroquinolinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, 5,6-dihydropyrrolo[1,2-b]pyrazolyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, thieno[2,3-b]pyrrolyl, furopyridinyl, thienopyridinyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dioxinyl, imidazo(2,1-b)(1,3)thiazole, and benzo-1,3-dioxolyl, phenyl, indenyl, and naphthyl.
 6. A compound according to claim 5, wherein R^(5a) is selected from: halogen, C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₂₋₁₀ alkynyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, (C₃₋₈)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, ((C₀₋₁₀)alkyl)₁₋₂aminocarbonyloxy, (C₀₋₁₀)heteroalkylaminocarbonyloxy, C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, (C₀₋₁₀)heteroalkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, aryl C₀₋₁₀alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, heteroarylC₀₋₁₀alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, (C₃₋₈)heterocycloalkylC₀₋₁₀alkylamino(oxy)₀₋₁carbonylC₀₋₁₀ alkyl, C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl (oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀ alkyl, —CO₂(C₀₋₁₀ alkyl), —(C₀₋₁₀ alkyl)CO₂H, Oxo (═O); C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, (C₃₋₈) cycloalkylsulfonyl, (C₃₋₈) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, —SO₂N(C₁₋₆alkyl)₁₋₂, —SO₂C₁₋₆alkyl, —SO₂CF₃, —SO₂CF₂H, —Si(CH₃)₃, (C₀₋₁₀ alkyl)₁₋₂ amino, hydroxy, (C₁₋₁₀ alkyl)OH, C₀₋₁₀ alkylalkoxy, cyano, (C₁₋₆alkyl)cyano, and C₁₋₆haloalkyl; wherein two R^(5a) and the atom to which they are attached may optionally form a −4, −5, or −6 member saturated ring system and wherein R^(5a) is each optionally substituted with 1, 2, 3, or 4 R⁶ substituents.
 7. A compound according to claim 6, wherein R^(5a) is independently selected from: tert-butyloxycarbonyl, fluoro, ethoxy, methoxy, methylsulfonyl, oxo, methoxycarbonyl, (methylamino)carbonyl, cyano, 2-hydroxypropanyl, hydroxyethyl, acetyl, methylcarbonyl, trifluoromethylcabonyl, methyl, pyrazolyl, amino, (trifluoromethyl)sulfonyl, (difluoromethyl)sulfonyl, hydroxymethyl, sulfamoyl, dimethylsulfamoyl, dimethylaminocarbonyl, trifluoromethyl, morpholinylcarbonyl, aminocarbonyl, chloro, 1,2,4-oxadiazolyl, cyclobutyloxy, ethoxycarbonyl, cyclopropyl, hydroxypropanyl, trifluoroethyl, bromo, methoxyoxoethyl, morpholinyl, isoxazolyl, phenyl, naphthalenyl, methylCOOH, trifluoroethyl, pyridinylmethyl, benzyl, cyanopropyl, napthalenylmethyl, cyclohexylmethyl, 1,3-benzodioxolylmethyl, propyl, methylsulfonyl, (2E)-3-phenylprop-2-enyl, benzofuranylmethyl, phenylprop-2-ynyl, imidazolylmethyl, pyrazolylmethyl, imidazo[I,2-a]pyridinylmethyl, pyrazinylmethyl, thiazoylmethyl, 1,3-thiazoylmethyl, tetrahydro-2H-pyranylmethyl, pyrazolo[1,5-a]pyridinylmethyl, pyrrolo[2,3-b]pyridinylmethyl, furanylmethyl, indolylmethyl, cyclobutylmethyl, 1,3-oxazolylmethyl, isoxazolymethyl, benzimidazolylmethyl, 4,5-dyhydroisoxazolylmethyl, phenylethyl, 1-phenylethyl, 2-fluoroethyl, methylsulfonyl, benzyloxycarbonyl, propyloxycarbonyl, cyclobutyloxycarbonyl, cyclobutylmethyloxycarbonyl, isopropyloxycarbonyl, tetrahydrofuranyloxycarbonyl, tetrahydropyranyloxycarbonyl, oxetanyloxycarbonyl, oxetanylmethyloxycarbonyl, propyloxycarbonyl, cyclopentyloxycarbonyl, cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, 2,3-dihydro-1H-indenyloxycarbonyl, pyridinylmethyloxycarbonyl, morpholinylethyloxycarbonyl, piperidinyloxycarbonyl, piperazinylethyloxycarbonyl, piperidinylmethyloxycarbonyl, ethyloxycarbonyl, cyclopropylmethyloxycarbonyl, naphthalenylethyloxycarbonyl, phenylethyloxycarbonyl, ethyloxycarbonyl, pyrrolidinylethyloxycarbonyl, pyridinylethyloxycarbonyl, pyridinylpropyloxycarbonyl, cyclopropylethyloxycarbonyl, ethylcarbonyl, (2E)-prop-2-enylcarbonyl methylcarbonyl, tert-butylcarbonyl, butylcarbonyl, methylcarbonyl, tetrahydrofuranylcarbonyl, pyridinylcarbonyl, pyrazinylcarbonyl, isoxazolylcarbonyl, cyclohexylcarbonyl, thiophenylcarbonyl, pyrrolidinylmethylcarbonyl, (1E)-ethylenylcarbonyl, phenylcarbonyl, indolylcarbonyl, benzylcarbonyl, naphthalenylcarbonyl, quinolinylcarbonyl, methylcarbonyl, tetrahydrofuranylmethylcarbonyl, methylethylcarbonyl, pyrazolylcarbonyl, cyclobutylcarbonyl, dimethylpropylcarbonyl, isopropylsulfonyl, furanylsulfonyl, tert-butylsulfonyl, phenylsulfonyl, imidazolylsulfonyl, cyclopropylsulfonyl, naphthalenylsulfonyl, trifluoromethylsulfonyl, phenylaminocarbonyl, cyclohexylaminocarbonyl, methylethylaminocarbonyl, butylaminocarbonyl, ethylaminocarbonyl, (1,1,3,3,-tetramethylbutyl)aminocarbonyl, phenylethylaminocarbonyl, azetidinyl, cyclohexylamino; phenylamino, pyridinylamino, tetrahydro-2H-pyranylamino, difluoromethylsulfonyl, ethylamino, cyclopropylmethylamino, methylamino, benzylamino, amino, tert-butylcarbonyl, 1,2,3,-tiazolyl, and tetrahydrofuranyloxycarbonyl; wherein two R^(5a) and the atom to which they are attached may optionally form a −4, −5, or −6 member saturated and wherein R^(5a) is each optionally substituted with 1, 2, 3, or 4 R⁶ substituents.
 8. A compound according to claim 6, wherein, X is selected from N and C.
 9. A compound according to claim 6, wherein X is selected from O and S.
 10. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
 11. A method for the treatment of a JAK-mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable thereof.
 12. A method of treating a condition in a mammal that can be ameliorated by the selective inhibition of a Janus kinase JAK1 relative to JAK 2 and JAK 3 which condition is selected from arthritis, asthma, obstructive airways diseases, autoimmune diseases or disorders, and cancer comprising administering to the mammal in need of such treatment, a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or a stereoisomer thereof.
 13. A method according to claim 12, wherein said condition is arthritis.
 14. A method according to claim 13, wherein said condition is selected from rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.
 15. A method according to claim 12, wherein said condition is asthma or obstructive airways diseases.
 16. A method according to claim 15, wherein said condition is selected from: chronic asthma, late asthma, airway hyper-responsiveness, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, recurrent airway obstruction, chronic obstruction pulmonary disease (COPD), and emphysema.
 17. A method according to claim 12, wherein said condition is autoimmune diseases or disorders.
 18. A method of treating asthma in a mammal in need thereof, comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 19. A method of treating arthritis in a mammal in need thereof, comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 